Conditions: Short Bowel Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if an investigational treatment (teduglutide) is safe and effective in Japanese children (age 4 months through 15 years of age) with SBS who are dependent on parenteral support. This study will also evaluate how teduglutide moves through the body (pharmacokinetics) and how it affects the body (pharmacodynamics).

Detailed description:

Arms:
arm 1: Participants will receive teduglutide 0.05 milligram per kilogram per day (mg/kg/day) subcutaneous (SC) injection once daily for 24 weeks.

Interventions: intervention 1: Teduglutide
Intervention descriptions: intervention 1: 0.05 mg/kg/day SC injection once daily for 24 weeks.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT02980666 
Study Title: 
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 4 Months Through 15 
Years, With Short Bowel Syndrome Who Are Dependent on Parenteral 
Support 
Study Number: 
SHP633-302 
Protocol Version and Date: 
Original Protocol: 
18 Dec 2015 
Amendment 1: 
27 Apr 2016 
Amendment 2: 
06 Jun 2017 
Amendment 3: 
24 Jan 2018 
Amendment 4: 
12 Jun 2018 
For non-commercial use only


Clinical Trial Protocol: SHP633-302
TITLE:
A 24-Week Safety, Efficacy, Pharmacodynamic, and 
Pharmacokinetic Study of Teduglutide in Japanese Pediatric 
Subjects through 15 Years of Age with Short Bowel Syndrome 
who are Dependent on Parenteral Support
NUMBER:
SHP633-302
PHASE:
3
DRUG:
Teduglutide 
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire, Inc. 
300 Shire Way
Lexington, MA  02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 18 Dec 2015
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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Shire 
Protocol SHP633-302 
CONFIDENTIAL 
Version 1.0, Final 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
J Signature: 
I 
, MD, PhD-=
,
, Clinical Medicine 
-1 Date: 
L_ 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-302. 
18 Dec 2015 
Page 2 of70 
Title: A 24-Week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects through 15 Years of Age with Short 
Bowel Syndrome who are Dependent on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents ofthis 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 or subject's legally-authorized representative in 
order to obtain their consent/assent 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 Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and 
Address: 
(please hand print or type) 
Signature: 
Date: 
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Protocol SHP633-302
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Page 3 of 70
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event, the investigator must fax or e-mail the Shire Clinical 
Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form within 
24 hours to the Shire Global Pharmacovigilance and Risk Management Department. 
Applicable fax numbers and e-mail address can be found on the form (sent under separate 
cover). A copy of this form must also be sent to the Shire Medical Monitor by fax or e-mail 
using the details below.
For protocol- or safety-related issues during normal business hours (Monday-Friday, 
9:00 AM to 5:00 PM, EST), the investigator should contact the Shire Medical Monitor:
, MD, PhD
, Clinical Medicine
Phone: 
Email:
Fax:
For protocol- or safety-related issues outside of normal business hours, the investigator 
should contact:
, MD
Phone: 
Email: 
 or 
SAE Fax Number: 
 or 
 (Japan domestic line only)
In-country Clinical Caretaker:
 
, 
: 
Quintiles Transnational Japan K.K
Phone: 
Email:
Fax:
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Page 4 of 70
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 adverse events related to product complaints, see 
Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed):
Shire (USA)
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TABLE OF CONTENTS
ABBREVIATIONS ...................................................................................................................8
STUDY SYNOPSIS ................................................................................................................10
STUDY SCHEDULES............................................................................................................17
1
BACKGROUND INFORMATION ................................................................................23
2
STUDY OBJECTIVES AND PURPOSE .......................................................................26
3
STUDY DESIGN.............................................................................................................27
4
STUDY POPULATION..................................................................................................29
4.4.1
Subject Withdrawal Criteria ........................................................................32
4.4.2
Reasons for Discontinuation........................................................................32
4.4.3
Subjects “Lost to follow-up” Prior to Last Scheduled Visit........................33
5
PRIOR AND CONCOMITANT TREATMENT ............................................................34
6
INVESTIGATIONAL PRODUCT..................................................................................35
6.1.1
Blinding of the Treatment Assignment........................................................35
6.2.1
Allocation of Subjects to Treatment ............................................................35
6.3.1
Labeling and Packaging...............................................................................36
6.3.2
Storage and Handling...................................................................................36
7
STUDY PROCEDURES .................................................................................................38
7.1.1
Screening......................................................................................................38
7.1.2
Treatment Period..........................................................................................38
7.1.3
Follow-up Period .........................................................................................38
7.2.1
Informed Consent.........................................................................................38
7.2.2
Study Entrance Criteria................................................................................39
7.2.3
Confirmation of Study Eligibility................................................................39
7.2.4
Demographics and Other Baseline Characteristics......................................39
7.2.5
Pharmacokinetic Assessments .....................................................................40
7.2.6
Pharmacodynamic/Efficacy Assessments....................................................40
7.2.7
Safety Assessments......................................................................................41
7.2.8
Gastrointestinal-specific Testing .................................................................43
7.2.9
Other Study Procedures ...............................................................................44
8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS .............................47
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse 
Events.....................................................................................................................47
8.1.1
Severity Categorization................................................................................47
8.1.2
Relationship Categorization.........................................................................48
8.1.3
Outcome Categorization ..............................................................................48
8.1.4
Symptoms of the Disease Under Study .......................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations......................................49
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8.1.6
Pregnancy.....................................................................................................49
8.1.7
Abuse, Misuse, Overdose, and Medication Error........................................50
8.2
Serious Adverse Event Procedures........................................................................50
8.2.1
Reference Safety Information......................................................................50
8.2.2
Reporting Procedures...................................................................................50
8.2.3
Serious Adverse Event Definition ...............................................................51
8.2.4
Serious Adverse Event Collection Time Frame...........................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates ...................................52
8.2.6
Fatal Outcome..............................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting ..............................................................................................52
9
DATA MANAGEMENT AND STATISTICAL METHODS ........................................55
9.4.1
Data Monitoring Committee........................................................................56
9.10.1
Pharmacokinetic Analyses...........................................................................58
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ....................................60
10.1.1
Good Clinical Practice Compliance.............................................................60
10.1.2
Public Posting of Study Information............................................................60
10.1.3
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees..............60
10.1.4
Study Suspension, Termination, and Completion........................................60
10.2.1
Good Clinical Practice Compliance.............................................................61
10.2.2
Protocol Adherence and Investigator Agreement........................................61
10.2.3
Documentation and Retention of Records...................................................61
10.3.1
Informed Consent.........................................................................................62
10.3.2
Institutional Review Board or Ethics Committee........................................63
11
LIST OF REFERENCES.................................................................................................66
APPENDIX 1
CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY ................................................................................67
APPENDIX 2
WEANING ALGORITHMS ......................................................................68
LIST OF IN-TEXT TABLES
Table 1
Study Schedule of Events – Screening to Week 12...................................17
Table 2 
Study Schedule of Events  – Weeks 13 to 28 ............................................20
Table 3
Blood Sample Collection Schedule for Pharmacokinetic Testing.............40
Table 4
List of Laboratory Tests.............................................................................42
Table 5
CTCAE Criteria for Teduglutide Adverse Events of Special Interest.......53
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LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram ..........................................................................................27
Figure A-1
Weaning Algorithm for Subjects Who Are NOT TOILET-TRAINED 
and in Diapers ............................................................................................68
Figure A-2
Subjects Who ARE TOILET-TRAINED and Not in Diapers...................69
Figure A-3 
Clinical Dehydration Assessment and PN/EN Adjustment.......................70
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-t
AUC from zero to the last measurable concentration
AUC0-inf
AUC of zero to infinity
AUCss
AUC at steady state
Cmax
maximum plasma concentration
Cmax,ss
Cmax at steady state
Cmin, ss
minimum plasma concentration at steady state
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EC
ethics committee
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
PN/IV
parenteral nutrition/intravenous fluid
SAE
serious adverse event
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SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2λz
terminal-phase half-life
tmax
time to Cmax
ULN
upper limit of normal
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STUDY SYNOPSIS
Protocol number: SHP633-302
Drug: Teduglutide
Study Title:
A 24-Week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects through 15 Years of Age, with Short Bowel 
Syndrome who are Dependent on Parenteral Support
Number of subjects: 
Planned enrollment is approximately 5 subjects.
Sites and Regions: Approximately 5 investigational sites in Japan are planned.
Study Duration:
There will be, at a minimum, a 2-week screening period followed by 24 weeks of 
treatment. The final site visit will be scheduled at Week 28, 4 weeks after the end of 
treatment (EOT) visit (Week 24).
Investigational Product, Dose, and Mode of Administration: 
During the treatment period, daily doses of 0.05 mg/kg/day of teduglutide will be 
administered subcutaneously (SC) to the subjects. The dose calculation will be based on 
body weight measured at the baseline visit (Visit 2) and adjusted, as needed, based on 
body weight measured at Week 12 (Visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with the sponsor’s medical monitor.
Objective(s): 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics (PD), and pharmacokinetics (PK) of teduglutide in pediatric subjects 
(through 15 years of age) with short bowel syndrome (SBS) who are dependent on 
parenteral support. 
Study Design:
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day 
of teduglutide. All subjects will be screened for a minimum of 2 weeks prior to start of 
treatment (SOT) to verify the requirements for nutritional support for each subject and to 
ensure adherence to eligibility parameters.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for 
the first 2 weeks (Weeks 1 and 2), and then every other week through Week 12 (Weeks 4, 
6, 8, 10, and 12). For the remainder of the treatment period, visits at the sites will be 
conducted every 3 weeks (at Weeks 15, 18, 21, and 24). Scheduled telephone contacts will 
be made on all other weeks during the treatment period. At all site visits and during 
telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. A final visit will be scheduled at Week 28, 4 weeks following EOT. 
Weekly telephone contact will be made during the interim weeks from EOT to end of 
study (EOS) to monitor safety and any changes in nutritional support.
To maintain consistency across all centers, the nutritional support adjustment guidelines 
(developed with SBS expert input and to be provided in the protocol) must be followed for 
decisions regarding parenteral nutrition/intravenous fluid (PN/IV) support reduction and 
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advances in enteral feeds based on weight gain, urine, and stool output in the setting of 
clinical stability.
Study Inclusion and Exclusion Criteria:
Male and female children and adolescents through 15 years of age who satisfy the 
following inclusion and exclusion criteria will be enrolled in the study.
Inclusion Criteria 
1. Informed consent by a parent or legally-authorized representative or emancipated 
minor prior to any study-related procedures
2. When applicable, an informed assent (as deemed appropriate by the Institutional 
Review Board) by the subject prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis).
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of 
caloric and/or fluid/electrolyte needs
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, 
usually associated with minimal or no advance in enteral feeds (ie, 10% or less change 
in PN or advance in feeds) for at least 3 months prior to and during screening, as 
assessed by the investigator. Transient instability for events such as interruption of 
central access or treatment of sepsis is allowed if the PN/IV support returns to within 
10% of baseline prior to the event.
6. Sexually active female subjects of childbearing potential must use medically 
acceptable methods of birth control during and for 4 weeks after the treatment period.
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed 
within 3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, 
Familial Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility disorders; that is the primary contributing 
factor to feeding intolerance and inability to reduce parenteral support, prior to 
screening. Dysmotility is defined as severe if it is expected to limit the advancement of 
enteral feeding.
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series 
done within 6 months prior to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection 
within 3 months prior to screening (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤ 10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease or congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair, and 
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patent ductus arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including 
resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and 
surgically resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 1 month or an experimental antibody treatment within 3 months 
prior to screening, or concurrent participation in any clinical study using an 
experimental drug that would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 
3 months prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 
3 months prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, 
antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months 
prior to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) 
within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support 
requirements within 1 month prior to or during screening, excluding uncomplicated 
treatment of bacteremia, central line replacement/repair, or issues of similar magnitude 
in an otherwise stable subject
19. Body weight <10 kg at the screening and baseline visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by 
any of the below laboratory test results during the screening period:
a.
Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 x ULN
c.
Alanine aminotransferase (ALT) ≥7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction 
shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2
22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of 
understanding or not willing to adhere to the study visit schedule and other protocol 
requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
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24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results. Examples of potential disease states/illnesses that may be 
excluded are listed below.
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active 
IBD 
which 
requires 
chronic 
systemic 
immunosuppressant therapy that had been introduced 
or changed during the last 3 months

IBD 
that 
requires 
chronic 
systemic 
immunosuppressant therapy for symptom control

Tufting or autoimmune enteropathy or microvillus 
inclusion disease

Untreated pre-malignant or malignant change in the 
GI tract identified by upper GI series, biopsy or 
polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba 
syndrome, 
Gardner’s 
syndrome, Cronkhite-Canada syndrome)

Intestinal or other major surgery scheduled within the 
time frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency 
syndrome, 
severe 
combined 
immunodeficiency)
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic 
diseases 
(eg, 
cardiovascular, 
respiratory, 
renal, 
infectious, endocrine, hepatic, or central nervous 
system)
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Pharmacokinetic Variables:
Blood samples for drug concentrations will be collected pre-dose, at 1 and 6 hours 
post-dose at start of treatment and at pre-dose, 2 and 4 hours post-dose at Week 4. If blood 
samples are not/cannot be collected at Week 4, the uncollected samples can be collected 
during any future site visit while the subject is still on investigational product. 
The following PK parameters will be derived using population PK analysis approach:

Area under the plasma concentration–time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Area under the concentration-time curve at steady-state (AUCss)

Maximum plasma concentration (Cmax)

Maximum plasma concentration at steady-state (Cmax,ss)

Minimum plasma concentration at steady-state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2λz)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Pharmacodynamic/Efficacy Assessments:
The primary PD parameter is PN/IV volume reduction of at least 20% at 24 weeks (or 
EOT) compared to baseline. 
Analysis of additional PD endpoints will include: 

100% reduction in PN/IV support  (any subjects who are able to completely wean off 
PN/IV support) compared to baseline at EOT

Change from baseline (absolute and percent change) in PN/IV support (volume and 
calories), plasma citrulline, and enteral nutritional support (volume and calories) over 
time

Change from Week 24 (or EOT) (absolute and percent change) in PN/IV support 
(volume and calories), plasma citrulline, and enteral nutritional support (volume and 
calories) at Week 28 (or EOS)

Change in body weight, height (or length), and head circumference (up to 36 months 
of age). Derived variables will include height Z-score, weight Z-score, body mass 
index (BMI), and BMI Z-score

Fecal output (by volume or number of bowel movements per day)

Change in hours per day and days per week of PN/IV support

Proportion of responders (ie, subjects who achieve at least a 20% reduction in PN/IV 
volume) over time 
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Safety 
Assessments:
Safety and tolerability will be assessed by evaluation of: 

Adverse events, including GI symptoms. A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline. GI symptoms will be 
recorded as none, mild, moderate, or severe. The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject.

Physical examinations 

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts

Electrocardiograms

Laboratory safety data, including clinical chemistries, hematology, and urinalysis

Changes in urine output (collected or calculated volume)

Fecal output (by volume or number of bowel movements per day)  

Antibodies to teduglutide. Samples for antibody analysis will be drawn at baseline and 
at the EOT (Week 24 or early termination visit) prior to the administration of 
teduglutide and at least 14 hours after the previous dose. One additional sample will be 
collected at the final visit 4 weeks after EOT (EOS, Week 28). If subjects are 
determined to have positive/specific antibodies at Week 28 or EOS, they will be asked 
to return for a follow-up site visit 3 months post EOT for another antibody sample. If 
the subjects continue to have positive/specific antibodies at 3 months post EOT, they 
will be asked to return for a follow-up site visit 6 months post-treatment in order to 
determine their antibody status. 

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, 
fecal occult blood testing, upper GI series with small bowel follow-through
Safety and tolerability will be evaluated by a Data Monitoring Committee during the study 
period.
Statistical Methods:
Due to the limited size of the study population descriptive statistics will be used with a 
goal of summarizing the sample. As such, no claims of significance will be made for any 
of the data. 
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, 
and the number and percentage of subjects in specified categories) will be presented, as 
appropriate, to summarize the demographic and baseline variables.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical 
variables, statistical summaries will include number of subjects and percentages.
Efficacy/pharmacodynamics data including reduction in PN/IV support, increase in 
enteral nutritional support, change in fecal output, change in plasma citrulline, weight 
Z-score, height Z-score, BMI Z-score, hours per day and days per week of PN/IV support, 
and time to PN/IV reduction and advance in enteral support will be summarized by visit 
and time point.
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Safety data including clinical laboratory tests, physical examinations, concomitant 
medications, electrocardiogram monitoring, and vital signs assessments will be 
summarized by visit and time point. Adverse events will also be collected and 
summarized. Descriptive statistics will be calculated for quantitative safety data as well as 
for the difference from baseline, if applicable. Frequency counts will be compiled for 
classification of qualitative safety data.
Date of Original Protocol: 18 December 2015
Date of Most Recent Protocol Amendment (if applicable): Not applicable
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18 Dec 2015
Protocol SHP633-302
Version 1.0, Final
Page 17 of 70
STUDY SCHEDULES
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed 
consent/assenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Dispense drugb
X
X
X
X
X
X
X
X
Dispense GI 
symptoms history 
worksheet
X
Review GI symptoms 
history worksheet
X
Upper GI with small 
bowel follow-
throughc
X
Abdominal 
ultrasoundc
X
Fecal occult blood 
testingd 
X
X
Colonoscopy/ 
sigmoidoscopyd
X
Plasma citrullinee
X
X
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
Review intake and 
X
X
X
X
X
X
X
X
X
X
X
X
X
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18 Dec 2015
Protocol SHP633-302
Version 1.0, Final
Page 18 of 70
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
output diariesf, g
Review nutritional 
support usage h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)i
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testingj
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs 
including weight
X
X
X
X
X
X
X
X
X
Height (length) and 
head circumferencek
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
testsl
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Antibodies to 
teduglutidem
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic 
sampling
Xn
Xo
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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18 Dec 2015
Protocol SHP633-302
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Page 19 of 70
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PN/IV=parenteral nutrition/intravenous fluid; SBS=short bowel syndrome; SC=subcutaneous 
a
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b
The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at least
4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF. The dose of study medication will be re-
evaluated at Week 12, based on weight gain/loss.
c
If they have not been performed within 6 months of the baseline visit, upper GI with small bowel follow through and abdominal ultrasound can be performed on all subjects 
at any time after signing of consent/assent but must be completed and results available and reviewed prior to the baseline visit. 
d
Fecal occult blood test will be performed on all subjects after signing of consent/assent. Colonoscopy/sigmoidoscopy will be conducted on all subjects 12 years of age and 
older and any subjects who have a positive fecal occult blood result without etiology to explain. Results of colonoscopies done within the prior year may also be used.
e
Plasma citrulline should be collected 2 to 4 hours postprandially, whenever possible.
f
Intake diaries will collect data on PN/IV support volume, EN, and other food and fluid intake daily throughout the study. 
g
Output diaries will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact. 
h
Nutritional support includes PN/IV, EN, and other food and fluid intake daily throughout the study. 
i
Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the 
guidance for nutrition support adjustment provided in Appendix 1 and Appendix 2.
j
Female subjects of childbearing potential  
k
Head circumference is to be collected as appropriate (ie, up to 36 months of age). 
l
At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. Safety lab assessments done between site visits approximately 7 days following 
any PN/IV adjustment consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety labs performed at alternate 
times in between site visits may be done locally and processed for submission to the central lab.
m
Antibody collection is to be done prior to first investigational product administration at study site.
n
Baseline (Visit 2) samples for PK analysis will be drawn predose and 1 and 6 hours postdose.
o
Week 4 (Visit 6) samples for PK analysis will be drawn predose and 2 and 4 hours postdose.
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Protocol SHP633-302
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Page 20 of 70
Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week 13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)k
Weeks 
25, 26, 
27l
Week 
28 (or 
EOS)
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Phone
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
175, 182, 
189
196
Visit Window 
(days)
2
2
2
2
2
2
2
2
2
2
2
2
2
4
Dispense drug
X
X
X
Fecal occult blood 
testinga
X
Colonoscopy/ 
sigmoidoscopya
(X)
Plasma citrullineb
X
X
Dispense intake and 
output diaries
X
X
X
X
Review intake and 
output diaries and 
nutritional support 
usage c d, e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)f
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testingg
X
X
X
X
X
Physical 
examination and 
vital signs, 
including weight
X
X
X
X
X
Height (length) and 
head circumferenceh
X
X
X
X
X
Electrocardiogram
X 
X
Safety laboratory 
testsi
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X) 
(X)
X
(X)
X
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Protocol SHP633-302
Version 1.0, Final
Page 21 of 70
Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week 13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)k
Weeks 
25, 26, 
27l
Week 
28 (or 
EOS)
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Phone
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
175, 182, 
189
196
Visit Window 
(days)
2
2
2
2
2
2
2
2
2
2
2
2
2
4
Antibodies to 
teduglutidej
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PN/IV=parenteral nutrition/intravenous fluid 
a
If fecal/occult blood is positive without explanation, then a colonoscopy/sigmoidoscopy may be warranted 
b
Plasma citrulline should be collected 2 to 4 hours postprandially, whenever possible.
c
Intake diaries will collect data on PN/IV support volume, EN, and other food and fluid intake daily throughout the study. 
d
Output diaries will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact.
e
Nutritional support includes PN/IV, EN feeds, and other food and fluid intake daily throughout the study. .
f
Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in appendix 1
Considerations for Management of Nutritional Support During the Study and appendix 2
Weaning 
Algorithms.
g
Female subjects of childbearing potential  
h
Head circumference is to be collected as appropriate (ie, up to 36 months of age). 
i
At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. Safety lab assessments done between site visits approximately 7 days following 
any PN/IV adjustment consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety labs performed at alternate 
times in between site visits may be done locally and processed for submission to the central lab.
j
Antibody blood draw is to be taken prior to the last dose of investigational product, at least 14 hours following the previous dose of investigational product. Subjects who test 
positive/specific for antibodies to teduglutide at the Week 28 visit will have follow-up blood draws for positive/specific antibodies to teduglutide at approximately 3 months 
following the last dose of investigational product. If antibodies are still positive/specific they will be collected again approximately 6 months after the last dose of 
investigational product. 
k
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later.
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Protocol SHP633-302
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Page 22 of 70
Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week 13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)k
Weeks 
25, 26, 
27l
Week 
28 (or 
EOS)
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Phone
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
175, 182, 
189
196
Visit Window 
(days)
2
2
2
2
2
2
2
2
2
2
2
2
2
4
l
A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an Unscheduled Visit.
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Page 23 of 70
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or 
severe intestinal disease that results in major surgical resections of the small intestine. In 
children, most cases of short bowel syndrome begin in infancy. Common causes of SBS in 
children include necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis 
(Duro et al, 2008; Squires et al, 2012). Similar to adults, new-onset SBS in older children 
usually stems from the Crohn’s disease, trauma, and cancer. The diminished absorptive 
capacity for fluids and nutrients often results in dependence on parenteral nutrition or 
intravenous fluids (PN/IV) to maintain energy and fluid and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus 
height and crypt depth, dilation, and delayed intestinal transit. The main principle of 
management of SBS is to provide the minimal necessary parenteral support to maintain energy, 
fluid, and electrolyte homeostasis while maximizing enteral feeding to promote intestinal 
adaptation. In infants, rapid linear growth of the intestines during the first year of life 
dramatically complements the aforementioned adaptive responses. About 30% of infants who 
develop SBS during the neonatal period become independent of PN/IV requirements by 
12 months of age, and an additional 10% wean off PN/IV support by 24 months of age. After 
this time, linear intestinal growth slows. About 60% of children with SBS are able to become 
independent of parenteral support by age 5 (Khan et al, 2015; Squires et al, 2012). 
Nevertheless, despite optimal medical management, many children remain dependent on 
PN/IV support.
Complications of long-term parenteral support include liver disease, catheter-related blood 
stream infections, central line-associated venous thrombosis and dwindling central venous 
access. Sepsis is the leading cause of death in these patients, and quality of life is poor. 
Accelerating the adaptive process is an urgent goal for all patients with SBS who are 
dependent on parenteral support.
For this reason, research in the pediatric arena is focused on children with PN/IV-dependent 
SBS. Given intestinal adaption in younger children, the unmet medical need is the greatest in 
children who are 1 year of age and older. It is highly unlikely that children with less than 10% 
of the expected length of small intestine reach enteral independence. These subjects reach a 
plateau in their ability to advance oral/enteral feeds or decrease PN/IV support (ie, are “stuck”) 
and are not expected to achieve spontaneous adaptation. Subjects who have not progressed to 
full enteral adaptation by 12 months after their intestinal insults are very unlikely to 
demonstrate spontaneous improvement in their enteral function (Sigalet et al, 2011). 
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide 2 (GLP-2), which is secreted from L-type 
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enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS. In the US and Europe, a GLP-2 analog called teduglutide is approved for the 
treatment of SBS in adult patients who are dependent on PN/IV support. 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like 
peptide-2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract. Teduglutide is a 33-amino acid peptide that differs from native 
GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus. As a 
result, teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and 
therefore maintains a longer elimination half-life 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 
(Thymann et al, 2014; Tappenden et al, 2013). 
Clinical Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries.
Two completed adult studies (CL0600-004 and its extension, CL0600-005) evaluated safety 
and tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were 
dependent on parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-
blind, placebo-controlled study in which 83 subjects were enrolled and 67 dosed with 
teduglutide, assessed the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in 
PN/IV. There was a statistically significant difference favoring the 0.05 mg/kg/day group over 
placebo (p=0.007) by using a graded response at the end of the study. At Week 24, the weekly 
reduction of PN/IV volume was similar in the 2 active groups (2.5 L each). The extension 
study, CL0600-005, assessed the long-term safety of teduglutide and the proportion of 
responders in the CL0600-004 study that maintained their response at the end of a further 
28 weeks of treatment. The extension study also assessed the effects of teduglutide at 28 weeks 
on those subjects previously receiving placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day dose, 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in 
PN/IV. Seventy-five percent of the subjects who previously responded to teduglutide treatment 
in Study CL0600-004 maintained this response or experienced further improved benefit from 
teduglutide treatment. More than 60% of the subjects previously receiving placebo in Study 
CL0600-004 achieved a clinical response after switching to teduglutide treatment for 6 months. 
The majority of adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which 
subjects were randomized to either teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The 
first stage of the study included a screening and optimization period and a stabilization period 
that demonstrated stable administration of PN/IV volume for a minimum of 4 weeks up to a 
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Page 25 of 70
maximum of 8 weeks. The second stage was a dosing period of 24 weeks. Subjects on 
0.05 mg/kg/day teduglutide achieved a higher responder rate (defined as a 20% to 100% 
reduction from baseline in PN/IV volume at Weeks 20 and 24) than the placebo-treated 
subjects (27/43 subjects, 62.8% and 13/43 subjects, 30.2%, respectively). This difference was 
clinically and statistically significant in both the Intention-to-Treat (ITT) (p=0.002) and Per 
Protocol (p < 0.001) populations. Generally, the incidence of treatment-emergent AEs 
(TEAEs) was distributed similarly across all treatment groups. The TEAEs with a higher 
incidence in the teduglutide group were mainly of GI origin. A long-term, open-label extension 
study (CL0600-021) assessed safety and efficacy for up to 24 additional months (ie, up to 
30 months of exposure for subjects who received teduglutide in Study CL0600-020). Overall, 
30 of 
43 subjects 
who 
received 
teduglutide 
in 
Study CL0600-020 
and 
entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide. Of these, 
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a 
PN/IV volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative 
to baseline prior to exposure to teduglutide at the beginning of Study CL0600-021. PN/IV use 
was reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 30 months 
of treatment. Of the 39 subjects who entered Study CL0600-021 after receiving placebo in 
Study CL0600-020, 29 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 3.11 L/week from baseline at the start of Study CL0600-021 (a 
28% reduction). Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction of 
parenteral support. Of the 12 subjects entering Study CL0600-021 directly, 6 completed 
24 months of treatment with teduglutide. The mean reduction in PN/IV volume was 
4.0 L/week (a 39.4% reduction from baseline at the start of Study CL0600-021) and 4 of the 
6 completers (66.7%) achieved a 20% or greater reduction of parenteral support.
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU 
countries. In this study, teduglutide was administered to 3 cohorts of children from age 1 
through 17. Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 
0.05 mg/kg/day for 12 weeks. Five additional children were enrolled in an observational 
standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at Week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at Week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts. 
There were no deaths during the study and no TESAEs related to teduglutide were reported. 
No discontinuations from study were due to adverse events. 
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Clinical Study 
Teduglutide was designated as an orphan drug indicated for SBS in Japan
on 
20 November 2014. Based on national surveys, it is estimated that the number of subjects with 
SBS who are dependent on parenteral nutrition/intravenous fluid (PN/IV) is less than 1000 in 
Japan. Among the 195 SBS subjects in the 2011 survey, 99 (51%) developed SBS at <1 years 
old (Takagi and Okada, 1993; Shirotani et al, 1996). Early intervention could potentially 
improve intestinal adaptation and decrease the need for parenteral support in these patients.
The current study proposes to investigate the safe and appropriate use of teduglutide in the 
Japanese 
pediatric 
population 
for 
the 
purpose 
of 
providing 
pharmacokinetic, 
pharmacodynamic, and safety data. This protocol was developed similarly to the planned 
EU/US 
study, 
TED-C14-006, 
A
24-Week 
Double-blind, 
Safety, 
Efficacy, 
and 
Pharmacodynamic Study Investigating Two Doses of Teduglutide in Pediatric Subjects 
through 17 Years of Age, with Short Bowel Syndrome who are Dependent on Parenteral 
Support. The TED-C14-006 protocol was developed with input from expert advisors from 
intestinal rehabilitation centers who offered advice on the most appropriate use of teduglutide 
in pediatric patients. The teduglutide dose of 0.05 mg/kg daily is supported by results from the 
completed 12 week pediatric study. The aim of teduglutide treatment is to increase absorptive 
capacity in order to yield decreases in parenteral support. In addition, the experts anticipated 
that there would be several direct benefits from decreased parenteral support and advances in 
enteral feeds, including less exposure to PN/IV constituents, less central line manipulation with 
lower risk of infection, and more time to focus on oral rehabilitation strategies.
2.2
Objective(s) 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics (PD), and pharmacokinetics (PK) of teduglutide in pediatric subjects 
(through 15 years of age) with short bowel syndrome (SBS) who are dependent on parenteral 
support. Refer to Section 9.8 and Section 9.10.1 for further details of the endpoints being 
measured.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of 
teduglutide. All subjects will be screened for a minimum of 2 weeks prior to start of treatment 
(SOT) to verify the requirements for nutritional support for each subject and to ensure 
adherence to eligibility parameters.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks (Weeks 1 and 2), and then every other week through Week 12 (Weeks 4, 6, 8, 10, 
and 12). For the remainder of the treatment period, visits at the sites will be conducted every 
3 weeks (at Weeks 15, 18, 21, and 24). Scheduled telephone contacts will be made on all other 
weeks during the treatment period. At all site visits and during telephone contacts, safety will 
be monitored and nutritional support will be reviewed and adjusted as needed. A final visit will 
be scheduled at Week 28, 4 weeks following EOT. Weekly telephone contact will be made 
during the interim weeks from EOT to end of study (EOS) to monitor safety and any changes 
in nutritional support. The Study Schedules are displayed at the beginning of this protocol.
To maintain consistency across all centers, the nutritional support adjustment guidelines 
(developed with SBS expert input and provided in Appendix 1 and Appendix 2) must be 
followed for decisions regarding parenteral nutrition/intravenous fluid (PN/IV) support 
reduction and advances in enteral feeds based on weight gain, urine, and stool output in the 
setting of clinical stability.
At the conclusion of the follow-up period (Week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post 
EOT for another antibody sample. If the subjects continue to have positive/specific antibodies at 
3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) 
periodically during the active study period, based on subject enrollment.
A schematic representation of the study design is displayed in Figure 1.
Figure 1
Study Diagram
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3.2
Study Duration
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment. 
Attempts should be made to limit the screening period to 4 weeks. The final site visit will be 
scheduled at Week 28, 4 weeks after the EOT visit (Week 24). 
The start of the clinical phase is defined as first subject consented. The end of the clinical 
phase is defined as the last visit of the last subject.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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4
STUDY POPULATION 
Approximately 5 male and female children and adolescents, through 15 years of age will be 
enrolled. 
4.1
Inclusion Criteria
1. Informed consent by a parent or legally-authorized representative or emancipated minor prior 
to any study-related procedures
2. When applicable, an informed assent (as deemed appropriate by the Institutional Review 
Board) by the subject prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis).
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment of sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
6. Sexually active female subjects of childbearing potential must use medically acceptable 
methods of birth control during and for 4 weeks after the treatment period.
4.2
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility disorders; that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within 
3 months prior to screening (insertion of feeding tube, anastomotic ulcer repair, minor 
intestinal resections ≤10 cm, or endoscopic procedure is allowed)
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8. Unstable cardiac disease or congenital heart disease  or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic GLP-2 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, 
antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at the screening and baseline visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results during the screening period:
a.
Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 x ULN
c.
Alanine aminotransferase (ALT) ≥7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of 
understanding or not willing to adhere to the study visit schedule and other protocol 
requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
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24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results. Examples of potential disease states/illnesses that may be excluded are listed 
below.
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced 
or changed during the last 3 months

IBD that requires chronic systemic immunosuppressant 
therapy for symptom control

Tufting or autoimmune enteropathy or microvillus 
inclusion disease

Untreated pre-malignant or malignant change in the GI 
tract identified by upper GI series, biopsy or 
polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome)

Intestinal or other major surgery scheduled within the 
time frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency)
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system)
4.3
Reproductive Potential 
Sexually active females of childbearing potential must be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
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contraceptives throughout the study period and for 4 weeks following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception, as defined below, if they become sexually 
active during the period of the study and 4 weeks following the last dose of investigational 
product. 
Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine and/or serum β-HCG pregnancy test 
at the Screening Visit (Visit 1) and prior to enrollment. Females of childbearing potential 
must agree to abstain from sexual activity (ie, true abstinence1) that could result in pregnancy 
or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms  

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the Screening Visit (Visit 1), plus condoms. Note: If subject becomes 
sexually active during the study, they should use one of the other acceptable methods noted 
above in addition to the hormonal contraceptive until it has been stabilized for 30 days.
4.4
Discontinuation of Subjects
4.4.1
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to further treatment. However, a discussion should be 
held 
by 
the 
investigator 
and 
the 
Shire 
Medical 
Monitor 
prior 
to
the 
patient 
discontinuing/withdrawing. 
4.4.2
Reasons for Discontinuation
Reasons for discontinuation may include but are not limited to:

Adverse event

Death

Failure to meet enrollment criteria
                                                
1   True abstinence: Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception).
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
Lost to follow-up

Non-compliance with investigational product

Physician decision

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Technical problems

Withdrawal by parent/legally-authorized representative

Withdrawal by subject
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. If the reason is not known, the subject must be 
followed-up to establish whether the reason was an adverse event (AE) and, if so, the AE must 
be reported in accordance with the procedures described in Section 8.1. Reasons for 
discontinuation other than AEs must be reported within 4 weeks of the EOS date in order to be 
included in the database. Any reason for discontinuation obtained after this time will be included 
in the subject’s medical record only unless the EOS visit date is amended and the database 
remains open.
To the extent possible, all examinations scheduled for the EOT evaluation must be performed on 
all subjects who participate, even if they do not complete the study according to the protocol.
Any subject who discontinues treatment prematurely will be asked to return 4 weeks later for the 
EOS visit and will be contacted weekly for wellness checks during the interim period between 
EOT and EOS.
4.4.3
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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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including non-prescription herbal treatments, vitamins, etc.) received 
within 14 days prior to the Screening Visit (Visit 1) and through the end of study (ie, including 
the protocol-defined follow-up period) must be recorded on the appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 14 days of the first dose of investigational 
product, but discontinued before the first dose of investigational product. 
5.2
Concomitant Treatment
Concomitant medications are those that continue after the start of investigational product or are 
newly introduced after the start of treatment through the end of study. In all instances the start 
date of prior and concomitant therapies must be recorded to the extent possible.
5.3
Prohibited Treatment
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
The following prior therapies are excluded within the timeframes noted (refer to Section 4.2).
Prior Therapy
Time Restriction Prior to 
Screening
Native/synthetic glucagon-like peptide-2
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Experimental antibody treatment
3 months
Biological therapy (eg, antitumor necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Teduglutide for subcutaneous (SC) injection is provided as a lyophilized powder that must be 
reconstituted using 0.5 mL with sterile water for injection. In addition to the active ingredient 
(teduglutide), each vial of teduglutide contains L-histidine, mannitol, monobasic sodium 
phosphate monohydrate, and dibasic sodium phosphate as excipients. Additional information is 
provided in the Investigator’s Brochure.
6.1.1
Blinding of the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product
Daily doses of 0.05 mg/kg/day of teduglutide will be administered to the subjects for 24 weeks. 
The dose calculation will be based on body weight measured at the baseline visit (Visit 2) and 
adjusted, as needed, based on body weight measured at Week 12 (Visit 14). No other 
adjustments to dose will be made during the study period, unless discussed with the sponsor’s 
medical monitor.
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For subjects 
with a stoma, the quadrant of the abdomen containing the stoma will not be used. Teduglutide 
should be used as soon as possible after reconstitution, but no more than 3 hours later.
The subject should be dosed at approximately the same time each day, preferably in the morning. 
If a dose is delayed, that day’s dose should be administered as soon as possible, but consecutive 
doses should be separated by at least 12 hours.
The first SC injection should be administered under the supervision of the investigator or 
designee and the subject observed for hypersensitivity reactions for at least 4 hours during their 
initial dosing visit. The site of administration (arm, thigh, abdomen) of the first teduglutide dose 
must be specified and recorded in the eCRF. Detailed instructions for reconstitution and injection 
of the investigational product can be found in the Instructions for Use. Each day, the injection 
site should be changed. 
6.2.1
Allocation of Subjects to Treatment 
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day as described in 
Section 6.2. Subject numbers are assigned to all subjects as consent/assent to take part in the 
study is provided. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. These 
numbers will be used to identify the subjects throughout the study period. Once a number/unique 
identifier has been assigned, that number must not be used again if, for example, a subject is 
withdrawn from the study. If a unique identifier is allocated incorrectly, the study monitor must 
be notified as soon as the error is discovered.
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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. Investigational product will be supplied in kits containing 7 vials and 
labeled with appropriate study information. Space will be provided on the label for recording 
study site and subject numbers at the study site. Ancillary supply kits containing syringes with 
needles for injection and reconstitution, sterile water, and alcohol swabs will also be provided.
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 to 8oC 
(35.6 to 46.4oF) until dispensed to a subject. Once dispensed to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25oC, or 35.6 to 77oF). Parent/legally-authorized representative will be instructed to keep the 
subject’s investigational product and sterile water diluent at controlled room temperature. If there 
are concerns that the controlled room temperature cannot be maintained, the investigational 
product may be refrigerated.
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.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the study visits at which the subject is required to be at 
the clinic. Each investigational product kit is sufficient for a treatment period of 1 week and 
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enough kits will be supplied to cover the period until the next planned study visit. Additional 
study kits will be provided as necessary.
Each subject will be given the investigational product according to his/her treatment assignment. 
The investigator is to keep a current record of the inventory and dispensing of all clinical
supplies. All dispensed medication will be documented on the eCRFs and/or other 
investigational product record. The investigator is responsible for assuring the retrieval of all 
study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to a 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. Returned investigational products must be packed in a tamper-evident manner to 
ensure product integrity. 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.
6.5
Treatment Compliance
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by asking the subject or the subject’s parent or 
legally-authorized representative if they have administered the investigational product according 
to instructions. If any doses have been missed, the reason for missed dose should be documented 
in the subject’s source documentation including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee prior to interrupting the 
subject’s daily investigational product dosing regimen for reasons such as hospitalization and 
adverse events, a lapse in investigational product delivery, etc. 
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. Subjects falling outside of these parameters will not be included in the per-protocol 
efficacy analyses (refer to Section 9.6).
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7
STUDY PROCEDURES
7.1
Study Schedule
Subject evaluations will be performed during the indicated days and weeks of the study as 
provided in the Study Schedules. 
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1.1
Screening
All subjects will be screened for a minimum of 2 weeks. Attempts should be made to limit the 
screening period to 4 weeks. All subjects’ parents/guardians must sign an informed consent and, 
if applicable, subjects must sign an informed assent form prior to initiation of any study-related 
procedure.
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigation product. 
At the discretion of the investigator, subjects who fail screening may be re-screened one time 
with prior sponsor approval. In the event of re-screening, a new subject number will be assigned.
7.1.2
Treatment Period
Subjects who pass all screening evaluations will be enrolled in the study and will receive the first 
dose of investigational product at the baseline visit (Visit 2). Subjects will enter a 24-week 
treatment period consisting of either visits or scheduled weekly telephone contacts as outlined in 
Section 3.1.
7.1.3
Follow-up Period
The follow-up period for this protocol is 4 weeks. At the end of this period (Week 28, EOS) 
there will be a follow-up visit to query for serious adverse events (SAEs), adverse events (AEs), 
and concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact 
will be followed to closure (see Section 8.1). As described in Section 3.1, weekly telephone 
visits will be conducted on the interim weeks between EOT and EOS.
7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (and, when 
applicable, informed assent) must be obtained from the subject’s parent(s) or legally authorized 
representative(s) and from the subject (if applicable).
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The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legally authorized representative 
by the investigator or designee in accordance with the guidelines described in Section 10.3.1. 
Documentation and filing of informed consent documents should be completed according to 
Section 10.2.
7.2.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria by 
the investigator or designee. Subjects who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the subject’s ineligibility for the study will 
be documented.
7.2.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at 
baseline by the investigator or designee on the basis of review of the study entrance criteria.
7.2.4
Demographics and Other Baseline Characteristics
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, sex, and race)

Medical history (including surgical history) and SBS history (including remnant anatomy) 
will be collected at the screening visit. 

SBS history, including remnant anatomy

Vital signs including temperature, heart rate, blood pressure, body weight, head circumference 
(up to 36 months of age), and height or length, and trends on growth chants 

Physical examination

Prior medications (medications used within 14 days prior to screening and discontinued prior 
to the first dose of investigational product), including drug name, dose, route, reason for use, 
and therapy dates. Medications used during the treatment period (after the first dose of 
investigational product) will be recorded as concomitant medications.

Electrocardiogram (12-lead) variables include general findings (normal/abnormal/abnormal, 
clinically significant). The cause of any clinically significant electrocardiogram (ECG) will 
be specified.

Laboratory test results: Serum chemistries, hematology, and urinalysis

Plasma citrulline levels

Presence of antibodies to teduglutide and titer level, if present
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
Gastrointestinal imaging (upper GI with small bowel follow through [UGI/SBFT], abdominal 
ultrasound, colonoscopy/sigmoidoscopy, fecal occult blood)

Pregnancy testing for females of childbearing potential

Nutritional support (eg, PN/IV and EN volume and calorie usage)

Data entered in the nutritional diaries
7.2.5
Pharmacokinetic Assessments
Blood samples for drug concentrations will be collected at baseline (prior to first teduglutide 
dose) and at Week 4. Pharmacokinetic assessments are listed in Section 9.10.1. A schedule of PK 
sample collection is provided in below in Table 3. Instructions for sample collection and 
handling are included in the laboratory manual.
Table 3
Blood Sample Collection Schedule for Pharmacokinetic Testing
Study Week
Baseline
Week 4
Visit Number
2
6
Hour
0a
1
6
0a
2
4
a Prior to investigational product administration
The time points indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these time points may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

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 (at the Week 4 draw).

1-hour postdose draw: ±5 minutes

2-hour postdose draw: ±5 minutes

4-hour postdose draw: ±5 minutes

6-hour postdose draw: ±5 minutes
The date and time of administration of the investigational product must be documented on the 
PK Blood Sampling eCRF.
7.2.6
Pharmacodynamic/Efficacy Assessments
Assessment of PD/efficacy parameters will be based on PN/IV volume, enteral nutritional 
support, fecal output, plasma citrulline, and changes in body weight, height (or length) and head 
circumference (up to 36 months of age). Pharmacodynamic endpoints are listed in Section 9.8.
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7.2.7
Safety Assessments
7.2.7.1
Physical Examination
Physical examinations will be performed by the principal investigator or designee. Any 
significant finding at baseline should be included in the subject’s medical history eCRF, 
including known lab abnormalities such as decreased hemoglobin as part of anemia, history of 
elevated liver enzymes, etc. Any clinically significant changes from baseline (in the opinion of 
the investigator) noted during the physical examinations, whether or not these procedures are 
required by the protocol, should be recorded on the appropriate AE page of the eCRF. This will 
assist the sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome.
7.2.7.2
Vital Signs
Vital signs will be measured according to the Study Schedules. Measurements will include 
temperature, heart rate, blood pressure, and body weight. Subjects should be weighed on the 
same scale at each study visit. Height (or length [cm]) and head circumference (in cm for 
subjects ≤36 months of age) will be measured at selected visits.
7.2.7.3
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing according to the Study Schedules. Subjects should be in a seated or supine position during 
blood collection.
Laboratory collections that are required at intervals that do not coincide with site visits (ie, for 
safety lab assessments done following PN/IV adjustments) may be obtained locally or at the 
investigational site. 
Clinical laboratory tests will include the following (refer to Table 4):
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Table 4
List of Laboratory Tests
Hematology:
-
Hematocrit 
-
Hemoglobin 
-
Platelet count
-
Red blood cell count 
-
White blood cell count with differential
-
RBC morphology, if needed 
Urinalysis: 
Blood
Glucose
Leucocytes
Microscopic analysis
Specific gravity
pH and osmolality
Protein
Sodium
Urine Pregnancy tests (females of childbearing 
potential)
Serum Chemistry:
-
Albumin 
-
Alkaline phosphatase 
-
Alanine aminotransferase 
-
Amylase
-
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
C-reactive protein 
-
Creatinine
Estimated Glomerular Filtration Rate 
(Schwartz formula)
-
Gamma-glutamyl transferase 
-
Glucose
-
Lipase
-
Magnesium
-
Phosphorus
-
Potassium 
-
Sodium 
-
Triglycerides
-
Uric acid
7.2.7.4
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the Study 
Schedules. Plasma citrulline should be collected 2 to 4 hours postprandially, whenever possible. 
Blood samples for citrulline may be drawn from a central line or peripheral access. The samples 
will be processed according to instructions in the Laboratory Manual. 
7.2.7.5
Antibody Assessments
Samples for antibody analysis will be drawn at baseline and at the EOT (Week 24 or early 
termination) visits prior to the administration of teduglutide and at least 14 hours after the 
previous dose. One additional sample will be collected at the final visit 4 weeks after the EOT 
(EOS, Week 28). If subjects are determined to have positive/specific antibodies at Week 28 or 
EOS, they will be asked to return for a follow-up site visit 3 months post EOT for another 
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antibody sample. If the subjects continued to have positive/specific antibodies at 3 months 
post-EOT, they will be asked to return for a follow-up visit 6 months post-treatment in order to 
determine their antibody status.
Blood samples for antibodies may be drawn from a central line or peripheral access. 
7.2.7.6
Pregnancy Testing
Any female subject in the study of childbearing potential must have a negative urine pregnancy 
test to enroll or continue in the study. Pregnancy tests will be performed at screening and at all 
site visits. 
7.2.7.7
Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study.
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than one blood assessment 
is to be done at the same time point, the assessments should be combined if they require the same 
type of tube.
7.2.7.8
Electrocardiogram
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) 
as indicated in the Study Schedules. Electrocardiogram recordings will be read locally by an 
experienced physician. Results (normal, abnormal not clinically significant, and abnormal 
clinically significant with a description of the abnormality) will be recorded on the eCRF. 
7.2.8
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during or prior to the screening period, as 
indicated below. Follow-up testing will be performed as necessary according to the guidelines 
noted below and the Study Schedules.
7.2.8.1
Upper Gastrointestinal Series with Contrast
An UGI/SBFT will be performed following the ingestion of barium contrast material. Results 
from procedures performed within 6 months prior to Visit 1 will also be acceptable.
7.2.8.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to Visit 1 will also be acceptable.
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7.2.8.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, Week 12, and at the end of treatment. 
Subjects with positive results for fecal occult blood for whom a cause is not readily identified 
(eg, anal fissure) will undergo a confirmatory colonoscopy/sigmoidoscopy. If no known 
underlying documented etiology can be attributed to this finding, the results should be discussed 
with the sponsor’s Medical Monitor.

Subjects with negative endoscopy findings may enroll in the study

Subjects with positive endoscopy findings who receive definitive treatment may enroll in the 
study

Subjects with positive endoscopy findings who do not receive definitive treatment will be 
excluded from the study

In those subjects with positive results for fecal occult blood at the end of the study, the 
investigator will have to determine the cause for the finding and may perform an additional 
colonoscopy/sigmoidoscopy, if clinically warranted.
7.2.8.4
Colonoscopy/Sigmoidoscopy
Subjects age 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening. 
Children under the age of 12 years may also undergo the procedure if they had a positive result 
on the fecal occult blood testing (see above). Results from procedures performed within 1 year 
prior to Visit 1 will also be acceptable for the screening measurement. 
7.2.9
Other Study Procedures
7.2.9.1
Nutritional Support Usage
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status which will include measures for weight, linear growth, hydration status, 
and safety laboratory results. The pharmacodynamic endpoints for this study include a ≥20% or 
greater reduction in PN/IV support guided by clinical status. A 20% decrease in PN/IV volume 
over 24 weeks is considered clinically meaningful to PN/IV-dependent children who have 
plateaued in their ability to wean PN/IV and advance their enteral feeds. A decrease of this 
magnitude may translate to several hours a day for more age-appropriate activities or an 
opportunity to introduce an extra oral feed to encourage oral rehabilitation. Guidance for 
nutrition support adjustment to be followed for this protocol is provided in Appendix 1 and 
Appendix 2. 
Evaluation of each subject’s nutritional support will be made during screening and every week 
during the study. The following information will be collected and can be used to evaluate each 
subject’s nutritional support: 

Daily PN/IV support volume, calories, and infusion duration as prescribed and as recorded 
by the subject/parent or legally-authorized representative
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
Daily enteral nutrition (EN) volume and calories (as prescribed and as recorded by the 
subject/parent or legally-authorized representative)

Other nutritional intake (regular diet and drink) 

48-hour urine output  and urine specific gravity prior to each phone and site visit 

48-hour stool output (by volume or daily stool count) and stool consistency, prior to each 
phone and site visit

Clinical chemistry and urinalysis

Weight trajectory (measured at site visits)
7.2.9.2
Diaries
Subjects or subjects’ parent or legally-authorized representative will be required to complete the 
following:

Intake diaries, completed daily, which will include:
o
PN/IV volume and calories (days per week, hours per day)
o
EN (formula and specialized electrolyte solutions) volume and calories (days per week, 
hours per day)
o
Other nutrition (regular diet and drink) intake (to be converted into calories by site 
personnel)

Urine/stool output diary, completed every day during the screening period and for 2 days (48 
hours) just prior to every scheduled visit and telephone contact, consisting of:
o
Collection of urine data:

For those who are toilet trained and NOT IN DIAPERS: All urine output should be 
measured and recorded in mL. The subject or parent/legally-authorized representative
will perform dipstick specific gravity tests on the first urine produced after the daily 
infusions of PN/IV support.

For those who are not toilet trained and IN DIAPERS: The weight of all urine-only 
diapers will be recorded. Volume will be calculated based on the formula: 1g (scale 
weight)=1 mL or 1 cc. At the discretion of the investigator, the parent/legally-
authorized representative may be asked to collect the first void after the daily infusion 
of PN/IV support to measure the specific gravity.
o
Collection of stool output data (including stool only and mixed urine/stool diapers):

For those who are toilet trained and NOT IN DIAPERS: Daily stool count will be 
recorded.

For those who are not toilet trained and IN DIAPERS: The weight of all diapers that 
contain stool (including diapers that contain mixed stool and urine) will be recorded 
as stool output. Stool volume will be calculated based on the formula: 1 g (scale 
weight=1 mL or 1 cc).
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
All ostomy output will be recorded as stool output and measured in cc or mL.

In addition all subjects (toilet trained or not) will record the consistency (form) of the 
stool passed each day during the 48-hour period prior to each visit. The 
subjects/parent or legally-authorized representative of subject will use the Bristol 
Stool Form Scale (Lewis and Heaton, 1997) to make the assessment.
All diaries will be reviewed by the investigator or their designee at each visit or telephone 
contact to assess clinical status and opportunity for PN/IV changes and advance in feeds. At each 
visit, the diaries will be reviewed for completeness and accuracy of the data.
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8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 7.1.3. This includes events occurring during the screening 
phase of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
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
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 
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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, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the 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 end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment 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, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
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 SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
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Products Pregnancy Report Form. The test date of the first positive serum/urine β-HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 0.05 mg/kg/day of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Investigator’s Brochure which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor or 
designee within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
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requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(refer to Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form 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) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire Medical Monitor or designee using the details specified in the 
emergency contact information section of the protocol. 
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed 
consent/assent is signed until the defined follow-up period stated in Section 3.2 and must be 
reported to the Shire Global Pharmacovigilance and Risk Management Department and the Shire 
Medical Monitor or designee within 24 hours of the first awareness of the event. 
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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent form, or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or designee are responsible for notifying the relevant regulatory authorities/ 
central institutional review boards (IRBs)/ethics committees (ECs) of related, unexpected SAEs. 
In addition the sponsor and/or designee is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the teduglutide program. 
The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
8.3
Adverse Events of Special Interest
Teduglutide administration for an individual subject may need to be stopped if the subject has an 
adverse event of special interest (refer to risks in table below) that is severe in intensity (Grade 3 
or higher as defined by the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events [CTCAE]). This may occur if an event is attributable to investigational product
or a subject experiences an unexplained CTCAE Grade 3 or higher that is not reasonably related 
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to the underlying disease process. The determination of length of the discontinuation, temporary 
or permanent, depends on the clinical situation. 
Investigators and the DMC should be guided by the descriptions of Grade 3 and 4 events, as they 
relate to identified risks associated with the administration of teduglutide (refer to Table 5).
Table 5
CTCAE Criteria for Teduglutide Adverse Events of Special Interest
Identified Risk
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent
intervention indicated
Intestinal Obstruction
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self-care activities of daily 
living; disabling
Life-threatening  consequences; urgent
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or
hospitalization indicated; nonemergent
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline Phosphatase 
increased
>5.0 to 20.0 x Upper limit of normal
>20.0 x Upper limit of normal
Blood bilirubin increased
>3.0 to 10.0 x Upper limit of normal
>10.0 x Upper limit of normal
Bile duct stenosis
Severely altered gastrointestinal 
function; radiologic, endoscopic or
elective operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
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Table 5
CTCAE Criteria for Teduglutide Adverse Events of Special Interest
Identified Risk
Grade 3 Description
Grade 4 Description
Pancreatic duct stenosis
Severely altered gastrointestinal 
function; tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase increaseda
>2.0 to 5.0 x Upper limit of normal
>5.0 x Upper limit of normal
Lipase increaseda
>2.0 to 5.0 x Upper limit of normal
>5.0 x Upper limit of normal
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; 
intervention indicated
Life-threatening consequences; urgent
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
a
In the setting of clinically acute and symptomatic pancreatitis 
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
The DMC may recommend stopping the study if:

≥2 subjects being administered investigational product develop the same CTCAE Grade 3; or

1 subject develops a CTCAE Grade 4 adverse event which is attributable to investigational 
product or is not reasonably related to the underlying disease process.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is enrolled, 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
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US Food and Drug Administration (FDA) 21 CFR Part 11 Guidance. The 
clinical trial database will include an audit trail to document any evidence of data processing or 
activity on each data field by each user. 
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Pharmacovigilance and Risk Management database.
9.3
Statistical Analysis Process
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.
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics.
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Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
All statistical analyses will be performed using SAS®.
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design.
9.4.1
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by Shire, independent contractors hired by Shire, or members of regulatory 
agencies. The DMC may make recommendations to Shire regarding stopping, modifying or 
continuing the study; however, Shire will have the final responsibility to determine whether the 
study should be modified or temporarily or permanently stopped. 
Safety and tolerability results will be evaluated by a DMC periodically during the active study 
period (date of the first subject’s first dose to date of the last subject’s last dose), based on 
subject enrollment. The DMC review will include all cumulative safety data (ie, adverse events, 
laboratory assessments, physical examinations, etc.) from study assessment through each cutoff 
period.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation.
9.6
Study Population
The ITT population is defined as any subjects who were enrolled into the study. The safety 
population is defined as the subset of ITT with subjects who received at least 1 administration of 
investigational product with any safety follow-up. The primary population analyzed for efficacy 
will be the ITT population. An additional per-protocol population analysis will also be performed 
as secondary/sensitivity analysis. The per-protocol population is defined as the subset of subjects 
in the ITT population without a major protocol deviation. Details will be prospectively defined in 
the final SAP prior to database lock.
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9.7
Demographics and Baseline Characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories) will be presented, as appropriate, to 
summarize the demographic and baseline variables.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized. 
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with specific histories 
will be summarized by system organ class and preferred term.
9.8
Efficacy/Pharmacodynamic Endpoints
The primary PD parameter is PN/IV volume reduction of at least 20% at 24 weeks (or EOT) 
compared to baseline. 
Analysis of additional PD endpoints will include: 

100% reduction in PN/IV support  (any subjects who are able to completely wean off PN/IV 
support) compared to baseline at EOT

Change from baseline (absolute and percent change) in PN/IV support (volume and calories), 
plasma citrulline, and enteral nutritional support (volume and calories) over time

Change from Week 24 (or EOT) (absolute and percent change) in PN/IV support (volume 
and calories), plasma citrulline, and enteral nutritional support (volume and calories) at 
Week 28 (or EOS)

Change in body weight, height (or length), and head circumference (up to 36 months of age). 
Derived variables will include height Z-score, weight Z-score, body mass index (BMI), and 
BMI Z-score

Fecal output (by volume or number of bowel movements per day)

Change in hours per day and days per week of PN/IV support

Proportion of responders (ie, subjects who achieve at least a 20% reduction in PN/IV 
volume) over time
No formal statistical test will be performed due the limited sample size.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
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9.9
Safety Analyses
The safety and tolerability variables include:

Adverse events, including GI symptoms. A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline. GI symptoms will be recorded 
as none, mild, moderate, or severe. The principal investigator will assess the aggregate diary 
entries to determine a baseline of GI symptoms for each subject.

Physical examinations 

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts 

Electrocardiograms

Laboratory safety data, including clinical chemistry, hematology, and urinalysis

Change in urine output (collected or calculated volume) and urine specific gravity

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal 
occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment-emergent AEs will be summarized by 
system organ class and preferred term. The number and percentage of subjects with AEs, SAEs, 
AEs that lead to discontinuation, investigational product-related AEs (determined by the 
investigator), and AEs that lead to death will be summarized. AEs will also be summarized with 
regard to intensity and relationship to investigational product. For AEs of special interest, the 
CTCAE grading system will be used as described in Section 8.3.
For laboratory tests, vital signs, body weight, ECG, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies.
9.10
Other Analyses
9.10.1
Pharmacokinetic Analyses
The following pharmacokinetic parameters will be derived using population PK analysis 
approach:

Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)
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
AUC from zero to the last measurable concentration (AUC0–t)

AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Cmax at steady state (Cmax,ss)

Minimum plasma concentration at steady state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2λz)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, 
geometric mean, the number and percentage of subjects in specified categories) will be 
calculated to summarize the absolute values and change from baseline at each scheduled visit.
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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, and the World Medical Association Declaration of Helsinki and its 
amendments concerning medical research in humans, as well as all applicable national and local 
laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
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10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor or designee before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent/assent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable 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
Case Report Forms
Electronic case report forms will be supplied by the sponsor or designee and should be handled 
in accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from
which accurate information is recorded onto eCRFs, which have been designed to record all 
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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 solely onto the eCRF.
All data transmitted to the sponsor or designee must be endorsed by the investigator. The study 
monitor will verify the contents against the source data per the monitoring plan. If the data are 
unclear or contradictory, queries will be sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to subject’s 
medical file, subject diaries, and original clinical laboratory reports, and imaging reports. All key 
data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the 
Pharmaceuticals and Medical Devices Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for
conducting the study, or other payments the investigator receives from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
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regulations and GCP. Each subject or the subject’s parent or legally-authorized representative, as 
applicable, is requested to sign and date the informed consent form/assent, or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent/assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent or legally-authorized representative, as applicable. This document may require 
translation into the local language. Signed consent/assent forms must remain in each subject’s 
study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form and assent 
form where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent
document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent
document (approved by the sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. Responsibility for coordinating with IRBs/ECs is defined in the 
investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor or designee has received 
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies 
this can be done by the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
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10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) 
which gave approval for the study to proceed. The sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11
LIST OF REFERENCES
Common Terminology Criteria for Adverse Events (CTCAE). US Department of Health and 
Human Services, National Institutes of Health, National Cancer Institute. Version 4.03, June 14, 
2010.
Duro D, Kamin D, Duggan C. Overview of Pediatric Short Bowel Syndrome. J Pediatr Gastro 
and Nutr 2008;47:S33-S36.
Khan FA, Squires RH, Litman HJ, et al. Predictors of enteral autonomy in children with 
intestinal failure: a multicenter cohort study. J Pediatr 2015 Jul;167(1):29-34.
Lewis SJ and Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924.
Shirotani N, Sato T, Fukushima T, et al. Annual report of national registration for home 
parenteral nutrition (HPN) in 1994. JPEN Research Journal 1996;11:262-265.
Sigalet D, Boctor D, Brindle M, Lam V, Robertson, M. Elements of successful intestinal 
rehabilitation. J Pediatr Surg 2011;46:150-156.
Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: 
initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012 Oct;161(4): 
723-728.
Takagi Y, Okada A. Home parenteral nutrition in Japan (National registration status survey in 
1991). J Clin Exp Cancer Med 1993;164(12):859-862.
Tappenden KA, Edelman J, Joelsson B. Teduglutide enhances structural adaptation of the small 
intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol 2013 Aug;
47(7):602-607.
Thymann T, Stoll B, Mecklenburg L, et al. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol 
Nutr 2014 Jun;58(6):694-702. 
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APPENDIX 1
CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric short bowel syndrome. These parameters should also be considered for managing 
nutritional support (PN/IV and/or oral/enteral feeding) in terms of volume and calories during 
the treatment period:

Considerations to adjust nutritional support in volume and calories will be made at all 
planned visits.

Maintaining growth (including weight and length and head circumference [for children up to 
36 months of age]) by the subjects trending along their growth chart and adjusting 
calories/volumes to maintain appropriate growth.

Other clinical evaluations
o
Serum electrolytes
o
BUN/creatinine levels
o
Change in stool frequency or volume, including mixed output
o
Stool consistency (ie, Bristol Stool Scale)
o
Urine specific gravity

General consideration to possible clinical deterioration in SBS
o
Inability to maintain weight and growth velocity
o
Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)
o
Colic/vomiting frequency increased
o
Electrolyte changes or imbalance
o
Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other oral fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.
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APPENDIX 2
WEANING ALGORITHMS  
Figure A-1
Weaning Algorithm for Subjects Who Are NOT TOILET-TRAINED and in 
Diapers
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18 Dec 2015
Protocol SHP633-302
Version 1.0, Final 
Page 69 of 70
Figure A-2
Subjects Who ARE TOILET-TRAINED and Not in Diapers
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Shire
CONFIDENTIAL
18 Dec 2015
Protocol SHP633-302
Version 1.0, Final 
Page 70 of 70
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment
For non-commercial use only


Clinical Trial Protocol: SHP633-302
TITLE:
A 24-week Safety, Efficacy, Pharmacodynamic, and 
Pharmacokinetic Study of Teduglutide in Japanese Pediatric 
Subjects, Aged 1 Year through 15 Years, with Short Bowel 
Syndrome who are Dependent on Parenteral Support
NUMBER:
SHP633-302
PHASE:
3
DRUG:
Teduglutide 
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421 USA
PROTOCOL 
HISTORY:
Amendment 1: 27 Apr 2016
Original Protocol: 18 Dec 2015
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


Shire 
Protocol SHP633-302 
CONFIDENTIAL 
Version 2.0 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
27 Apr 2016 
Page 2 of77 
r Signature: 
Date: 
 
, MD, Ph'
 
_J 
, Clinical Medicine______ 
-·---·------··--------· 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-302. 
Title: A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 1 Year through 15 Years, 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 or subject's legally-authorized representative in 
order to obtain their consent/assent 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 Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and 
Address: 
(please hand print or type) 
Signature: 
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CONFIDENTIAL
Page 3
Protocol SHP633-302
27 Apr 2016
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Age range for subjects has been specified. Subjects will be 1 year through 
15 years of age. 
Title page
Protocol signature page
Synopsis
Sections 4 and 4.1
Emergency contact information has been updated.
Emergency Contact Information
Sections 8.1.6, 8.2.2, 8.2.4
Clarification that departing from the nutritional support adjustment 
guidelines and weaning algorithms in Appendix 2 and Appendix 3, 
respectively, will not constitute a protocol deviation. 
Synopsis
Section 3.1
Statement added that subjects who complete the study may participate in a 
long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Section 3.1
Inclusion and Exclusion criteria have been refined and clarified; there were 
no criteria added with the exception of the age of subject population which 
has been added as an inclusion criterion (was previously in introductory 
sentence).
Synopsis
Sections 4.1 and 4.2
Exclusion Criterion #11 has been updated to indicate that a subject would 
be excluded from the study if the subject had participated in a clinical study 
of experimental drug within 3 months or 5.5 half-lives of the experimental 
drug, whichever is longer.
Synopsis
Section 4.2
Efficacy/PD endpoints have been lumped together and clarified. The small 
population does not warrant primary versus secondary endpoints. The 
statistical method has been clarified.
Synopsis
Section 9.8
Safety assessments and statistical methods have been clarified. 
Synopsis
Section 9.9
Study schedule of events tables have been revised to reflect the changes to 
the protocol and for clarity.
Table 1
Table 2
Any phone contacts may be replaced with unscheduled site visits if 
necessary.
Table 1
Table 2
Section 3.1
Requirement added that female subjects of child-bearing potential undergo 
a serum-based pregnancy test at screening.
Table 1
Table 2
Sections 4.3, 7.2.8, 7.2.11
Definition of prior and concomitant medications has been expanded to 
include invasive and diagnostic procedures.
Table 1
Table 2
Section 5
Additional information on selection of teduglutide dosing regimen and 
duration in the study has been inserted.
Section 2.1
Frequency of Data Monitoring Committee meetings has been specified.
Sections 3.1 and 9.4.1
Definition of screening period has been clarified.
Section 3.2
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Page 4
Protocol SHP633-302
27 Apr 2016
Inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy for symptom control has been removed from 
the list of excluded disease and illness in Exclusion Criterion #24.
Section 4.2 (Table 3)
Definition of acceptable methods of contraception has been revised to 
reflect available methods in Japan.
Section 4.3
List of prohibited prior therapy has been revised to remove experimental 
antibody treatment, as it is now included in the revised exclusion 
criterion #11.
Section 5.3
Requirement that teduglutide should be administered in the morning has 
been removed.
Section 6.2
Language on labeling, packaging, and drug accountability has been 
clarified.
Sections 6.3 and 6.4
Reviewing subject diaries has been included in the subject compliance with 
dosing check. Clarification that attempts should be made by the investigator 
to contact the sponsor or designee prior to dose interruption has been 
added.
Section 6.5
Requirement has been added that subjects who are re-screened must be re-
consented.
Section 7.1.1
Timeframe for a subject to be considered enrolled in the study has been 
clarified.
Sections 7.1.2 and 9.6
Demographics and other baseline characteristics have been clarified.
Section 7.2.4
Windows for PK blood collection have been extended; possibility to collect 
week 4 timepoint at any future visit if needed has been added.
Section 7.2.5
PT/INR testing has been added at screening and subsequently if confirmed 
drug-induced liver injury (DILI) is suspected thereafter.
Table 1
Table 2
Section 7.2.8
For children in diapers, urine specimen collection should be attempted as 
part of the safety lab assessments, but lack of urinalysis will not constitute a 
protocol deviation.
Table 1
Table 2
Section 7.2.8
Timeframe of follow-up for subjects with blood samples testing positive for 
anti-teduglutide antibodies at week 28 or EOS has been clarified.
Synopsis
Table 1
Table 2
Section 7.2.10
Need for a subject with a positive fecal occult blood testing at week 12 
without a readily identifiable cause by physical examination to undergo a 
colonoscopy or sigmoidoscopy is now open to discussion with the Shire 
medical monitor or designee.
Table 1
Table 2
Section 7.2.14.3
Need for children younger than 12 years to undergo a colonoscopy or 
sigmoidoscopy if they test positive for fecal occult blood at screening and 
the cause is not identified by physical examination has been specified.
Section 7.2.14.4
GI symptoms history worksheet has been renamed GI-specific symptoms 
history diary, and details on recording and reviewing symptoms have been 
added. 
Table 1
Table 2
Section 7.2.15.1
“Other nutrition (regular diet and drink)” has been removed from the Intake 
diary.
Section 7.2.15.2
Output diary data collection will continue to occur over a 48-hour period of 
PN/IV and EN stability before every site visit. Between site visits, the 
output diary collection will only be required within 1 week of 
Table 1
Table 2
Section 7.2.15.3
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CONFIDENTIAL
Page 5
Protocol SHP633-302
27 Apr 2016
implementing a change in the PN/IV prescription.
Severity categorization has been updated to specify that the severity of AEs 
listed in Table 6 that may lead to dose interruption based on known risks of 
teduglutide will also be evaluated using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grading criteria.
Section 8.1.1
Definition of an overdose to teduglutide has been revised.
Section 8.1.7
Adverse events of special interest have been redefined and procedures for 
reporting them have been added.
Section 8.3
More information has been provided on criteria for dose interruption of 
individual subjects. Dose discontinuation has been made absolute for an AE 
known to be a risk associated with teduglutide administration (Table 6) that 
is of NCI CTCAE severity ≥Grade 3 and considered to be related to 
investigational product; cases of severe hypersensitivity that are determined 
to be related to investigational product; DILI that is related to 
investigational product; and pregnancy. SAEs related to investigational 
product are potential but not absolute reasons for dose discontinuation.
Sections 8.4, 8.4.1, and 8.4.2
Criteria for DILI have been added.
Section 8.4.2
Criteria for early termination of the study have been clarified.
Section 8.5
Clarification that original diary data should be entered into the eCRF and 
take precedence over data collected over the phone.
Section 9.1
Definition of PK analysis population has been added.
Section 9.6
Pharmacokinetic analyses methods and parameters have been clarified.
Synopsis
Section 9.10.1
Protocol history has been added in Appendix 1.
Appendix 1
Guidelines for nutritional support management during the study have been 
clarified.
Appendix 2
See Appendix 1 for protocol history, including all amendments.
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CONFIDENTIAL
Page 6
Protocol SHP633-302
27 Apr 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event, the investigator must fax or e-mail the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to Quintiles Transnational Japan K.K using the details 
below. Applicable fax numbers and e-mail address can also be found on the form (sent under 
separate cover). 
In-country Clinical Caretaker:
 
, 
: 
Quintiles Transnational Japan K.K
Phone: 
Email:
Fax:
Pharmacovigilance SAE Reporting:
FAX: 
 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 between 8:00 to 20:00 US Eastern Standard 
Time, the investigator may contact the Shire medical monitor:
, MD, PhD
, Clinical Medicine
Office Phone: 
Mobile Phone: 
Email:
Fax: 
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CONFIDENTIAL
Page 7
Protocol SHP633-302
27 Apr 2016
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 adverse events related to product complaints, see Section 
8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed):
Shire (USA)
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Page 8
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27 Apr 2016
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF IN-TEXT TABLES ........................................................................................................11
LIST OF IN-TEXT FIGURES.......................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULES..................................................................................................................18
1
BACKGROUND INFORMATION.......................................................................................23
1.1
Indication and Current Treatment Options...............................................................23
1.2
Product Background and Clinical Information ........................................................23
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Clinical Study...............................................................................26
2.2
Objective(s) ..............................................................................................................26
3
STUDY DESIGN ...................................................................................................................27
3.1
Study Design and Flow Chart ..................................................................................27
3.2
Study Duration .........................................................................................................28
3.3
Sites and Regions .....................................................................................................28
4
STUDY POPULATION.........................................................................................................29
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................32
4.4
Discontinuation of Subjects .....................................................................................32
4.4.1
Subject Withdrawal Criteria ..................................................................................32
4.4.2
Reasons for Discontinuation..................................................................................32
4.4.3
Subjects “Lost to follow-up” Prior to Last Scheduled Visit..................................33
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................34
5.1
Prior Treatment ........................................................................................................34
5.2
Concomitant Treatment............................................................................................34
5.3
Prohibited Treatment................................................................................................34
6
INVESTIGATIONAL PRODUCT ........................................................................................35
6.1
Identity of Investigational Product...........................................................................35
6.1.1
Blinding of the Treatment Assignment..................................................................35
6.2
Administration of Investigational Product ...............................................................35
6.2.1
Allocation of Subjects to Treatment ......................................................................35
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27 Apr 2016
6.3
Labeling, Packaging, and Storage............................................................................36
6.3.1
Labeling and Packaging.........................................................................................36
6.3.2
Storage ...................................................................................................................36
6.4
Drug Accountability.................................................................................................36
6.5
Treatment Compliance .............................................................................................37
7
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening................................................................................................................39
7.1.2
Treatment Period....................................................................................................39
7.1.3
Follow-up Period ...................................................................................................39
7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Informed Consent...................................................................................................39
7.2.2
Study Entrance Criteria..........................................................................................40
7.2.3
Confirmation of Study Eligibility..........................................................................40
7.2.4
Demographics and Other Baseline Characteristics................................................40
7.2.5
Pharmacokinetic Assessments ...............................................................................41
7.2.6
Physical Examination (Including Height and Weight)..........................................41
7.2.7
Vital Signs..............................................................................................................42
7.2.8
Clinical Laboratory Tests.......................................................................................42
7.2.9
Plasma Citrulline....................................................................................................43
7.2.10 Antibody Assessments...........................................................................................43
7.2.11 Pregnancy Testing..................................................................................................44
7.2.12 Volume of Blood....................................................................................................44
7.2.13 Electrocardiogram..................................................................................................44
7.2.14 Gastrointestinal-specific Testing ...........................................................................44
7.2.14.1
Upper Gastrointestinal Series with Contrast ..........................................44
7.2.14.2
Abdominal Ultrasound ...........................................................................44
7.2.14.3
Fecal Occult Blood Testing....................................................................44
7.2.14.4
Colonoscopy/Sigmoidoscopy.................................................................45
7.2.15 Other Study Procedures .........................................................................................45
7.2.15.1
GI-specific Symptoms History...............................................................45
7.2.15.2
Nutritional Support.................................................................................45
7.2.15.3
Diaries ....................................................................................................45
8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ....................................47
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................47
8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................48
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8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Symptoms of the Disease Under Study .................................................................49
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................49
8.1.6
Pregnancy...............................................................................................................49
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................50
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................50
8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................52
8.2.6
Fatal Outcome........................................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................52
8.3
Adverse Events of Special Interest...........................................................................52
8.4
Dose Interruption of Individual Subjects .................................................................53
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide.......................53
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury...........................55
8.5
Early Termination of the Clinical Study ..................................................................56
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................57
9.1
Data Collection.........................................................................................................57
9.2
Clinical Data Management.......................................................................................57
9.3
Statistical Analysis Process......................................................................................57
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......58
9.4.1
Data Monitoring Committee..................................................................................58
9.5
Sample Size Calculation and Power Considerations................................................58
9.6
Study Population ......................................................................................................58
9.7
Demographics and Baseline Characteristics ............................................................59
9.8
Efficacy/Pharmacodynamic Analyses......................................................................59
9.9
Safety Analyses........................................................................................................59
9.10
Other Analyses .........................................................................................................60
9.10.1 Pharmacokinetic Analyses.....................................................................................60
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................62
10.1
Sponsor’s Responsibilities .......................................................................................62
10.1.1 Good Clinical Practice Compliance.......................................................................62
10.1.2 Public Posting of Study Information......................................................................62
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................62
10.1.4 Study Suspension, Termination, and Completion..................................................62
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10.2
Investigator’s Responsibilities .................................................................................63
10.2.1 Good Clinical Practice Compliance.......................................................................63
10.2.2 Protocol Adherence and Investigator Agreement..................................................63
10.2.3 Documentation and Retention of Records.............................................................63
10.2.3.1
Case Report Forms.................................................................................63
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................64
10.2.3.3
Financial Disclosure...............................................................................64
10.3
Ethical Considerations..............................................................................................64
10.3.1 Informed Consent...................................................................................................64
10.3.2 Institutional Review Board or Ethics Committee..................................................65
10.4
Privacy and Confidentiality......................................................................................65
10.5
Study Results/Publication Policy .............................................................................66
11 LIST OF REFERENCES........................................................................................................68
12 APPENDICES ........................................................................................................................69
LIST OF IN-TEXT TABLES
Table 1
Study Schedule of Events – Screening to Week 12...................................18
Table 2 
Study Schedule of Events  – Weeks 13 to 28 ............................................21
Table 3
Examples of Excluded Diseases and Illnesses...........................................31
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing.............41
Table 5
List of Laboratory Tests.............................................................................43
Table 6
Adverse Events that May Lead to Dose Interruption.................................53
LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram ..........................................................................................28
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in 
Diapers .......................................................................................................71
Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers................................72
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment.......................73
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-inf
AUC of zero to infinity
AUC0-t
AUC from zero to the last measurable concentration
AUCss
AUC at steady state
BMI
body mass index
Cmax
maximum plasma concentration
Cmax,ss
Cmax at steady state
Cmin, ss
minimum plasma concentration at steady state
CL/F
apparent clearance
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EC
ethics committee
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
US Food and Drug Administration
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GCP
Good Clinical Practice
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
IgM
immunoglobulin M
INR
international  normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
NCI
National Cancer Institute
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
PN/EN
parenteral nutrition/ intravenous fluids and enteral nutrition
PN/IV
parenteral nutrition/intravenous fluids
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow-through
ULN
upper limit of normal
US
United States
Vλz/F
apparent volume of distribution
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STUDY SYNOPSIS
Protocol number: SHP633-302
Drug: Teduglutide
Study Title:
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of Teduglutide in Japanese 
Pediatric Subjects, Aged 1 Year through 15 Years, with Short Bowel Syndrome who are Dependent on 
Parenteral Support
Number of subjects: 
Planned enrollment is approximately 5 subjects.
Sites and Regions: Approximately 5 investigational sites in Japan are planned.
Study Duration:
There will be, at a minimum, a 2-week screening period followed by 24 weeks of   treatment. The end of 
study (EOS) visit will be scheduled at week 28, 4 weeks after the end of treatment (EOT) visit (week 24).
Investigational Product, Dose, and Mode of Administration: 
During the treatment period, a dose of 0.05 mg/kg/day of teduglutide will be administered once daily
subcutaneously (SC) to the subjects. The dose calculation will be based on body weight measured at the 
baseline visit (visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with Shire medical monitor or designee.
Objective(s): 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and pharmacodynamics 
(PD), and pharmacokinetics (PK) of teduglutide in pediatric subjects (1 year through 15 years of age) with 
short bowel syndrome (SBS) who are dependent on parenteral support. 
Study Design:
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of teduglutide. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the requirements 
for nutritional support for each subject and to ensure adherence to eligibility parameters. Attempts should be 
made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the first 2 weeks 
(weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, and 12). For the remainder 
of the treatment period, visits at the sites will be conducted every 3 weeks (at weeks 15, 18, 21, and 24). 
Scheduled telephone contacts will be made on all other weeks during the treatment period. At all site visits 
and during telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. The EOS visit will be scheduled at week 28, 4 weeks following EOT. Weekly telephone 
contact will be made during the interim weeks from EOT to EOS to monitor safety and any changes in 
nutritional support.
To maintain consistency across all centers, all attempts should be made to follow the nutritional support 
adjustment guidelines and weaning algorithms (developed with SBS expert input and to be provided in the 
protocol) for decisions regarding parenteral nutrition/intravenous fluids (PN/IV) support reduction and 
advances in enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
Any departure from the nutritional support adjustment guidelines and weaning algorithms will not constitute 
a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have positive/specific 
antibodies, they will be asked to return for a follow-up visit 3 months post EOT for another antibody 
sample. If the subjects continue to have positive/specific antibodies at 3 months post EOT, they will be 
asked to return for follow-up visit(s) up to 6 months post-treatment in order to determine their antibody 
status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee periodically during the 
active study period, based on subject enrollment.
All subjects who complete the study may participate in a long term extension study in which eligible 
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subjects could receive teduglutide.
Study Inclusion and Exclusion Criteria:
Subjects who satisfy the following inclusion and exclusion criteria will be enrolled in the study. 
Inclusion Criteria 
1.
Informed consent by a parent or legally-authorized representative prior to any study-related procedures
2.
When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the 
subject prior to any study-related procedures 
3.
Male or female child or adolescent aged 1 year through 15 years
4.
Current history of SBS as a result of major intestinal resection (eg, due to necrotizing enterocolitis, 
midgut volvulus, intestinal atresia, or gastroschisis)
5.
Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or 
fluid/electrolyte needs
6.
Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually associated 
with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at 
least 3 months prior to and during screening, as assessed by the investigator. Transient instability for 
events such as interruption of central access or treatment of sepsis is allowed if the PN/IV support 
returns to within 10% of baseline prior to the event.
7.
Sexually active female subjects of childbearing potential must use medically acceptable methods of 
birth control during and for 4 weeks following the last dose of investigational product
Exclusion Criteria
1.
Subjects who are not expected to be able to advance oral or tube feeding regimens 
2.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of 
screening 
3.
Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and 
inability to reduce parenteral support 
4.
Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5.
Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
6.
Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done within 6 months 
prior to screening
7.
Major GI surgical intervention including significant intestinal resection within 3 months prior to 
screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections ≤ 10 cm, or 
endoscopic procedure is allowed)
8.
Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation 
9.
History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous 
basal or squamous cell carcinoma, or in situ non-aggressive and surgically resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 
3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to screening and for the 
duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to 
screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to 
screening 
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15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, antitumor 
necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant 
therapy that had been introduced or changed during the 3 months prior to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-related catheter 
sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the 
screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements within 1 
month prior to or during screening, excluding uncomplicated treatment of bacteremia, central line 
replacement/repair, or issues of similar magnitude in an otherwise stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the screening
period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d.
Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results 
of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of understanding or 
not willing to adhere to the study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results. Examples 
of potential disease states/illnesses that may be excluded are listed in Table 3.
Pharmacokinetic Variables:
Blood samples for drug concentrations will be collected at the baseline visit (predose, at 1 and 6 hours 
postdose) and at week 4 visit (predose, 2 and 4 hours postdose). If blood samples are not/cannot be collected 
at week 4, the uncollected samples can be collected during any future site visit while the subject is still on 
investigational product. 
The following PK parameters will be derived using a population PK modeling approach:

Area under the plasma concentration–time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)

Area under the concentration-time curve at steady-state (AUCss)

Maximum plasma concentration (Cmax)

Maximum plasma concentration at steady-state (Cmax,ss)

Minimum plasma concentration at steady-state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Efficacy/Pharmacodynamic Assessments:
The efficacy/PD endpoints include:

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), citrulline, 
and enteral nutritional support (volume and calories), separately, at each visit 
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
Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) compared 
to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
Safety Assessments:
Safety and tolerability will be assessed by evaluating the following: 

Adverse events, including those pertaining to GI symptoms. 

Physical examinations, including body weight, height (or length), head circumference (up to 36 months 
of age), and trends on growth charts

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms (ECGs)

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)  

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal occult blood 
testing, upper GI series with small bowel follow-through
Safety and tolerability will be evaluated by a Data Monitoring Committee during the study period.
Statistical Methods:
Due to the limited size of the study population, descriptive statistics will be used with a goal of summarizing 
the sample. As such, no claims of significance will be made for any of the data. 
Pharmacokinetic parameters will be estimated based on measured teduglutide plasma concentrations using a 
population PK modeling approach.
Continuous variables will be summarized using descriptive statistics including number of subjects, mean, 
median, standard deviation, maximum, and minimum. For categorical variables, statistical summaries will 
include number of subjects and percentages.
Efficacy/PD data will include change in PN/IV support, enteral nutritional support, plasma citrulline, and 
hours per day and days per week of PN/IV support, and will be summarized by visit.
Safety data will include clinical laboratory tests results; measurement of body weight, height (or length), and 
head circumferences (if applicable); vital signs; concomitant medications; and ECG monitoring; and will be 
summarized by visit. Adverse events will also be collected and summarized. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from baseline, if applicable. Frequency 
counts will be compiled for classification of qualitative safety data.
Date of Original Protocol: 18 Dec 2015
Date of Most Recent Protocol Amendment (if applicable): 27 Apr 2016
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STUDY SCHEDULES
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Informed 
consent/assenta
X
Eligibility
X
X
Demographics 
X
Medical /surgical 
history
X
Electrocardiogram
X
X
SBS history
X
Upper GI with small 
bowel follow-through
and abdominal 
ultrasoundb
X
Fecal occult blood 
testingc
X
X
Colonoscopy/ 
sigmoidoscopyc
(X)
(X)
Provide GI-specific 
symptoms history diary
X
Review GI-specific 
symptoms history diary
X
Dispense 
investigational productd
X
X
X
X
X
X
X
X
Pharmacokinetic 
sampling
Xe
Xf
Safety laboratory testsg
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testingh
X
X
X
X
X
X
X
X
X
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Plasma citrullinei
X
X
Antibodies to 
teduglutidej
X
Provide intake and 
output diaries
X
X
X
X
X
X
X
X
X
Review diaries and 
nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Physical examination/ 
vital signs/weight
X
X
X
X
X
X
X
X
X
Height (or length) and 
head circumferencem
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PK=pharmacokinetic; PT/INR=prothrombin time/international normalized ratio; 
PN/IV=parenteral nutrition/intravenous fluids; SBS=short bowel syndrome; SC=subcutaneous; UGI/SBFT= upper GI series with small bowel follow through
a
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b
If the subject has undergone an UGI/SBFT and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable for the 
screening assessments. If the subject has not had these procedures within the 6 months before visit 1 (screening), then the procedure(s) will be performed any time after 
providing informed consent with the results available and reviewed before the baseline visit (day 0).
c
All subjects enrolled will have a fecal occult blood test after providing consent/assent. Subjects with positive fecal occult blood test at screening for whom a readily 
detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or sigmoidoscopy. Colonoscopy or sigmoidoscopy will be conducted at screening on all 
subjects 12 years of age and older; however if the screening fecal occult blood test is negative and the subject has undergone the procedure within 1 year before visit 1 
(screening), then that result will be acceptable for the screening assessment (Section 7.2.14.4). Subjects with positive fecal occult blood test results at week 12 for which a 
cause is not identified by a physical exam will be discussed with the Shire medical monitor or designee (Section 7.2.14.3).
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
d
The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at 
least 4 hours. The site of administration (arm, thigh, abdomen) must be specified and recorded in the eCRF. The dose of study medication may be adjusted at week 12.
e
Baseline (visit 2) samples for PK analysis will be drawn predose, and 1 and 6 hours postdose (Section 7.2.5).
f
Week 4 (visit 6) samples for PK analysis will be drawn predose, and 2 and 4 hours postdose (Section 7.2.5).
g
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits (eg, 
biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine testing thereafter.  
i
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
j
Blood sample for antibody testing is to be collected at study site prior to first investigational product administration. Blood samples may be drawn from a central line or 
peripheral access (Section 7.2.10).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
m
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6).
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)
a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
P
hone 
Site
Phone
Site
Study day
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Dispense investigational 
product
X
X
X
Provide intake and output 
diaries
X
X
X
X
Review diaries and 
nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testsd
  (X)
  (X)
X
   (X)
   (X)
X
   (X)
   (X)
X
   (X) 
   (X)
X
      (X)
X
Pregnancy testinge
X
X
X
X
X
Plasma citrullinef
X
X
Antibodies to teduglutideg
X
X
Physical examination/
vital signs/weight
X
X
X
X
X
Height (or length) and 
head circumferenceh
X
X
X
X
X
Fecal occult blood testingi
X
Colonoscopy/ 
sigmoidoscopyi
(X)
Electrocardiogram
X 
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)
a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
P
hone 
Site
Phone
Site
Study day
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Concomitant medication/
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PN/IV=parenteral nutrition/intravenous fluid
a
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
d
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits 
(eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy (urine testing). 
f
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
g
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, at least 14 hours after the previous dose of teduglutide. If a blood sample is positive for 
antibodies at week 28 or EOS, then the subject will be retested 3 months after EOT. If that sample is positive, then the subject will be retested 6 months after EOT. 
h
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
i
Subjects with positive fecal occult blood test at week 24 (EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory 
colonoscopy or sigmoidoscopy (Section 7.2.14.3).
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease that results in major surgical resections of the small intestine. In children, most 
cases of short bowel syndrome begin in infancy. Common causes of SBS in children include 
necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. (Duro et al. 2008; 
Squires et al. 2012) Similar to adults, new-onset SBS in older children usually stems from 
Crohn’s disease, trauma, and cancer. The diminished absorptive capacity for fluids and nutrients 
often results in dependence on parenteral nutrition or intravenous fluids (PN/IV) to maintain 
energy and fluid and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus height 
and crypt depth, dilation, and delayed intestinal transit. The main principle of management of 
SBS is to provide the minimal necessary parenteral support to maintain energy, fluid, and
electrolyte homeostasis while maximizing enteral feeding to promote intestinal adaptation. In 
infants, rapid linear growth of the intestines during the first year of life dramatically 
complements the aforementioned adaptive responses. About 30% of infants who develop SBS 
during the neonatal period become independent of PN/IV requirements by 12 months of age, and 
an additional 10% wean off PN/IV support by 24 months of age. After this time, linear intestinal 
growth slows. About 60% of children with SBS are able to become independent of parenteral 
support within 5 years. (Khan et al. 2015; Squires et al. 2012) Nevertheless, despite optimal 
medical management, many children remain dependent on PN/IV support.
Complications of long-term parenteral support include liver disease, catheter-related blood 
stream infections, central line-associated venous thrombosis and dwindling central venous 
access. Sepsis is the leading cause of death in these patients, and quality of life is poor. 
Accelerating the adaptive process is an urgent goal for all patients with SBS who are dependent 
on parenteral support.
For this reason, research in the pediatric arena is focused on children with PN/IV-dependent 
SBS. Given intestinal adaption in younger children, the unmet medical need is the greatest in 
children who are 1 year of age and older. It is highly unlikely that children with less than 10% of 
the expected length of small intestine reach enteral independence. These subjects reach a plateau 
in their ability to advance oral/enteral feeds or decrease PN/IV support (ie, are “stuck”) and are 
not expected to achieve spontaneous adaptation. Subjects who have not progressed to full enteral 
adaptation by 12 months after their intestinal insults are very unlikely to demonstrate 
spontaneous improvement in their enteral function. (Sigalet et al. 2011)
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide-2 (GLP-2), which is secreted from L-type 
enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
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There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS. In the US and Europe, a GLP-2 analog called teduglutide is approved for the treatment 
of SBS in adult patients who are dependent on PN/IV support. 
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 compared to the native peptide, which has a t1/2 of 
approximately 7 minutes. Teduglutide has been shown in animal studies and previous human 
clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines. (Tappenden et al. 2013; Thymann et al. 
2014)
Clinical Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries. Two 
completed adult studies (CL0600-004 and its extension, CL0600-005) evaluated safety and 
tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were dependent 
on parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, 
placebo-controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, 
assessed the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was 
a statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study. At week 24, the weekly reduction of PN/IV 
volume was similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, 
assessed the long-term safety of teduglutide and the proportion of responders in the CL0600-004 
study that maintained their response at the end of a further 28 weeks of treatment. The extension 
study also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in 
PN/IV. Seventy-five percent of the subjects who previously responded to teduglutide treatment 
in Study CL0600-004 maintained this response or experienced further improved benefit from 
teduglutide treatment. More than 60% of the subjects previously receiving placebo in Study 
CL0600-004 achieved a clinical response after switching to teduglutide treatment for 6 months. 
Most of the adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus
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13/43 subjects [30.2%], respectively). This difference was clinically and statistically significant 
in both the intent-to-treat (ITT) (p=0.002) and per-protocol (p < 0.001) populations. Generally, 
the incidence of treatment-emergent AEs was distributed similarly across all treatment groups. 
The treatment-emergent AEs with a higher incidence in the teduglutide group were mainly of GI 
origin. A long-term, open-label extension study (CL0600-021) assessed safety and efficacy for 
up to 24 additional months (ie, up to 30 months of exposure for subjects who received 
teduglutide in Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in 
Study CL0600-020 and entered Study CL0600-021 completed a total of 30 months of treatment 
with teduglutide. Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral 
support resulting in a PN/IV volume reduction of 7.55 L/week, corresponding to a mean 
reduction of 65.6% relative to baseline prior to exposure to teduglutide at the beginning of 
Study CL0600-020. PN/IV use was reduced by at least 1 day per week in 21 of 30 subjects 
(70%) who completed 30 months of treatment. Of the 39 subjects who entered 
Study CL0600-021 after receiving placebo in Study CL0600-020, 29 completed 24 months of 
treatment with teduglutide. The mean reduction in PN/IV volume was 3.11 L/week from baseline 
at the start of Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support. Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support.
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU countries. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts. 
There were no deaths during the study and no treatment-emergent AEs related to teduglutide 
were reported. No discontinuations from study were due to AEs. 
Additional information is provided in the investigator’s brochure.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Clinical Study 
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014. 
Based on national surveys, it is estimated that the number of subjects with SBS who are 
dependent on parenteral nutrition/intravenous fluid (PN/IV) is less than 1000 in Japan. (Kitajima 
et al. 2013; Takagi et al. 1995; Takehara 2001) Among the 195 SBS subjects in the 2011 survey, 
99 (51%) developed SBS at <1 years old. Early intervention could potentially improve intestinal 
adaptation and decrease the need for parenteral support in these patients.
The current study proposes to investigate the safe and appropriate use of teduglutide in the 
Japanese pediatric population for the purpose of providing pharmacokinetic, pharmacodynamic, 
and safety data. This protocol was developed similarly to the planned EU/US study, TED-C14-
006, A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic Study Investigating Two 
Doses of Teduglutide in Pediatric Subjects through 17 Years of Age, with Short Bowel Syndrome 
who are Dependent on Parenteral Support. The TED-C14-006 protocol was developed with 
input from expert advisors from intestinal rehabilitation centers who offered advice on the most 
appropriate use of teduglutide in pediatric patients. The teduglutide dose of 0.05 mg/kg daily is 
supported by results from the completed 12-week pediatric study. Teduglutide is approved for 
adult use in the US and EU at a dose of 0.05 mg/kg SC once daily. The completed 12-week 
pediatric study (TED-C13-003, A 12-Week Pharmacokinetic, Safety, and Pharmacodynamic 
Study of Teduglutide in Pediatric Subjects Aged 1 Year through 17 Years, with Short Bowel 
Syndrome who are Dependent on Parenteral Support) demonstrated that teduglutide dosing at 
0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk profile. In addition, 
population pharmacokinetics (PK) modeling and simulations were conducted to determine the 
effective dose to be used in pediatric subjects using data from 8 adult clinical studies including 
adult Phases 1, 2, and 3 studies as well as the pediatric study (TED-C13-003); they suggested 
that the dose in pediatric subjects is likely to be the same as the dose in adults. (O'Keefe et al. 
2006) The duration of teduglutide treatment in study SHP633-302 mirrors that of the TED-C14-
006 study, consisting of 24 weeks of teduglutide treatment, followed by a 4-week follow-up 
period.
The aim of teduglutide treatment is to increase absorptive capacity in order to yield decreases in 
parenteral support. In addition, the experts anticipated that there would be several direct benefits 
from decreased parenteral support and advances in enteral feeds, including less exposure to 
PN/IV constituents, less central line manipulation with lower risk of infection, and more time to 
focus on oral rehabilitation strategies.
2.2
Objective(s) 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics (PD), and PK of teduglutide in pediatric subjects (1 year through 15 years of 
age) with SBS who are dependent on parenteral support. See Sections 9.8 and 9.10.1 for further 
details of the endpoints being measured, and Section 9.9 for safety variables.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of 
teduglutide. All subjects will be screened for a minimum of 2 weeks prior to start of treatment to 
verify the requirements for nutritional support for each subject and to ensure adherence to 
eligibility parameters. Attempts should be made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks (weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, 
and 12). For the remainder of the treatment period, visits at the sites will be conducted every 
3 weeks (at weeks 15, 18, 21, and 24). Scheduled telephone contacts will be made on all other 
weeks during the treatment period. At all site visits and during telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed. The end of study 
(EOS) visit will be scheduled at week 28, 4 weeks following end of treatment (EOT). Weekly 
telephone contact will be made during the interim weeks from EOT to EOS to monitor safety and 
any changes in nutritional support. The Study Schedules are displayed at the beginning of this 
protocol.
A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as 
an unscheduled visit.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines and weaning algorithms (developed with SBS expert input and 
provided in Appendix 2 and Appendix 3, respectively) for decisions regarding PN/IV support 
reduction and advances in enteral feeds based on weight gain, urine, and stool output in the 
setting of clinical stability. Any departure from the nutritional support adjustment guidelines and 
weaning algorithms will not constitute a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post EOT 
for another antibody sample. If the subjects continue to have positive/specific antibodies at 
3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) which 
will convene approximately every 3 months during the active study period, based on subject 
enrollment.
All subjects who complete the study may participate in a long term extension study in which 
eligible subjects could receive teduglutide.
A schematic representation of the study design is displayed in Figure 1.
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Figure 1
Study Diagram
EOS=end of study; EOT=end of treatment 
3.2
Study Duration
There will be, at a minimum, a 2-week screening period from the time of the screening visit to 
the baseline visit, followed by 24 weeks of treatment. Attempts should be made to limit the 
screening period to 4 weeks. The EOS visit will be scheduled at week 28, 4 weeks after the EOT 
visit (week 24). 
The start of the clinical phase is defined as first subject consented. The end of the clinical phase 
is defined as the last visit of the last subject.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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4
STUDY POPULATION 
Approximately 5 pediatric Japanese subjects, male and female children and adolescents aged 
1 year through 15 years, will be enrolled. 
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Informed consent by a parent or legally-authorized representative prior to any study-related 
procedures
2. When applicable, informed assent (as deemed appropriate by the Institutional Review Board) 
by the subject prior to any study-related procedures 
3. Male or female child or adolescent aged 1 year through 15 years 
4. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
5. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs
6. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment of sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
7. Sexually active female subjects of childbearing potential must use medically acceptable 
methods of birth control during and for 4 weeks following the last dose of investigational 
product
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
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6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease or congenital heart disease  or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic GLP-2 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, 
antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
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22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of 
understanding or not willing to adhere to the study visit schedule and other protocol 
requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results. Examples of potential disease states/illnesses that may be excluded are listed in 
Table 3.
Table 3
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in the GI tract 
identified by upper GI series, biopsy or polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug abuse within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease
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4.3
Reproductive Potential 
Sexually active females of childbearing potential must be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 4 weeks following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception if they become sexually active during the 
period of the study and 4 weeks following the last dose of investigational product. 
Female children and adolescent subjects should be either:
Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or
Females of childbearing potential with a negative serum β-HCG pregnancy test at the screening 
visit (visit 1) and a negative urine β-HCG pregnancy test prior to enrollment. Females of 
childbearing potential must agree to abstain from sexual activity (ie, true abstinence) that could 
result in pregnancy or agree to use medically acceptable methods of contraception at all times 
during the study and 4 weeks following the last dose of investigational product.
Note: True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception).
4.4
Discontinuation of Subjects
4.4.1
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to further treatment. However, a discussion should be 
held by the investigator and the Shire medical monitor or designee prior to the subject
discontinuing or withdrawing. 
4.4.2
Reasons for Discontinuation

Reasons for discontinuation may include but are not limited to:

Adverse event

Death

Failure to meet enrollment criteria

Lost to follow-up

Non-compliance with investigational product

Physician decision

Pregnancy

Protocol deviation

Site terminated by sponsor
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
Study terminated by sponsor

Technical problems

Withdrawal by parent/legally-authorized representative

Withdrawal by subject
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 8.1. 
To the extent possible, all examinations scheduled for the EOT evaluation must be performed on 
all subjects who participate even if they do not complete the study according to the protocol (ie, 
early termination). Any subject who discontinues treatment prematurely will be asked to return 
4 weeks later for the EOS visit and will be contacted weekly for wellness checks during the 
interim period between EOT and EOS.
4.4.3
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 timepoint prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including non-prescription herbal treatments, vitamins, invasive and 
diagnostic procedures) received within 14 days prior to the screening visit (visit 1) and through 
the end of study (ie, including the protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 14 days of the first dose of investigational 
product, but discontinued before the first dose of investigational product. 
5.2
Concomitant Treatment
Concomitant medications are those that continue after the start of investigational product or are 
newly introduced after the start of treatment through the end of study. In all instances the start 
date of prior and concomitant therapies must be recorded to the extent possible.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
Changes in any medication and/or dosage will be recorded on the eCRF. See also nutritional 
support in Section 7.2.15.2.
5.3
Prohibited Treatment
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The following prior therapies are excluded within the timeframes noted (see Section 4.2).
Prior Therapy
Time Restriction Prior to 
Screening
Native/synthetic glucagon-like peptide-2
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy (eg, antitumor necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Teduglutide for subcutaneous (SC) injection is provided in 3 mL vials containing 5 mg or 
1.25 mg teduglutide as a lyophilized powder that must be reconstituted using 0.5 mL with sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the investigator’s brochure.
6.1.1
Blinding of the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product
A dose of 0.05 mg/kg/day of teduglutide will be administered once daily to the subjects for 
24 weeks. The dose calculation will be based on body weight measured at the baseline visit 
(visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with the Shire medical monitor or designee.
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. If a dose is delayed, that 
day’s dose should be administered as soon as possible, but consecutive doses should be separated 
by at least 12 hours.
The first SC injection should be administered under the supervision of the investigator or 
designee and the subject observed for hypersensitivity reactions for at least 4 hours during their 
initial dosing visit. The site of administration (arm, thigh, abdomen) of the first teduglutide dose 
must be specified and recorded in the eCRF. Detailed instructions for reconstitution and injection 
of the investigational product can be found in the Instructions for Use. Each day, the injection 
site should be rotated. 
6.2.1
Allocation of Subjects to Treatment 
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day as described in 
Section 6.2. Subject numbers are assigned to all subjects as consent/assent to take part in the 
study is provided. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. These 
numbers will be used to identify the subjects throughout the study period. Once a number/unique 
identifier has been assigned, that number must not be used again if, for example, a subject is 
withdrawn from the study. If a unique identifier is allocated incorrectly, the study monitor must
be notified as soon as the error is discovered.
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6.3
Labeling, Packaging, and Storage
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.
The pre-filled sterile water for injection syringes used for the reconstitution of the investigational 
product will also be provided. The pre-filled sterile water for injection syringes will be labeled in 
accordance with the applicable regulatory requirements. The dosing syringes and needles for 
reconstitution will be provided separately.
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practices.
6.3.2
Storage
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 and 8oC
until dispensed to a subject. The pre-filled sterile water for injection syringes will be stored at a 
temperature between 2 and 25°C. Once dispensed/supplied to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25oC). Parent/legally-authorized representative will be instructed to keep the subject’s 
investigational product and sterile water diluent at controlled room temperature. If there are 
concerns that the controlled room temperature cannot be maintained, the investigational product
may be refrigerated.
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.
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The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the study visits at which the subject is required to be at 
the clinic. Each investigational product kit is sufficient for a treatment period of 1 week and 
enough kits will be supplied to cover the period until the next planned study visit. Additional 
study kits will be provided as necessary.
Each subject will be given the investigational product according to his/her treatment assignment. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. All dispensed medication will be documented on the eCRFs and/or other 
investigational product record. The investigator is responsible for assuring the retrieval of all 
study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects. 
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.
See the Pharmacy Manual for additional information.
6.5
Treatment Compliance
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by reviewing the subject diaries and asking the subject or 
the subject’s parent or legally-authorized representative if they have administered the 
investigational product according to instructions. If any doses have been missed, the reason for 
missed dose should be documented in the subject’s source documentation including, as 
applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
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Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. Subjects falling outside of these parameters will not be included in the per-protocol 
efficacy analyses (see Section 9.6).
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7
STUDY PROCEDURES
7.1
Study Schedule
Subject evaluations will be performed during the indicated days and weeks of the study as 
provided in the Study Schedules. 
All data collected are to be recorded on the appropriate eCRF.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1.1
Screening
All subjects’ parents/legally-authorized representatives must sign an informed consent form and, 
if applicable, subjects must sign an informed assent form prior to initiation of any study-related 
procedure. All subjects will be screened for a minimum of 2 weeks. Attempts should be made to 
limit the screening period to 4 weeks.
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigation product. 
At the discretion of the investigator, subjects who fail screening may be re-screened one time 
with prior sponsor approval. In the event of re-screening, a new subject number will be assigned
to the subject and the subject will also be re-consented.
7.1.2
Treatment Period
Subjects who meet all eligibility criteria at screening, and eligibility criteria are confirmed at 
visit 2/baseline, will be enrolled in the study and will receive the first dose of investigational 
product at the baseline visit (visit 2). Subjects will enter a 24-week treatment period consisting of 
either visits or scheduled weekly telephone contacts as outlined in the Section 3.1.
7.1.3
Follow-up Period
During the 4-week follow-up period, weekly telephone visits will be conducted on week 25 to 
week 27 followed by the EOS visit (week 28). Similar to assessments performed during the 
treatment period, phone visits during follow-up will include review of intake diaries, and 
adjustment of nutritional support as needed (see Section 3.1). Procedures to be performed at the 
EOS visit (week 28) are specified in the Study Schedules; subjects will be queried on serious 
adverse events (SAEs), AEs, and concomitant treatments, and all AEs and SAEs that are not 
resolved at the time of this visit will be followed to closure (see Section 8.1).
7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (and, when 
applicable, informed assent) must be obtained from the subject’s parent(s) or legally authorized 
representative(s) and from the subject (if applicable).
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The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legally authorized representative 
by the investigator or designee in accordance with the guidelines described in Section 10.3.1. 
Documentation and filing of informed consent documents should be completed according to 
Section 10.2.
7.2.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria by 
the investigator or designee. Subjects who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the subject’s ineligibility for the study will 
be documented.
7.2.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at 
baseline by the investigator or designee on the basis of review of the study entrance criteria.
7.2.4
Demographics and Other Baseline Characteristics
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy

GI-specific symptoms history (Section 7.2.15.1)

Physical examination, including body weight, height (or length), and head circumference (up 
to 36 months of age), and trends on growth charts

Vital signs including temperature, heart rate, and blood pressure

Prior medications (medications used within 14 days prior to screening and discontinued prior 
to the first dose of investigational product), including drug name, dose, route, reason for use, 
and therapy dates. Medications used during the treatment period (after the first dose of 
investigational product) will be recorded as concomitant medications.

Electrocardiogram (ECG) (12-lead) variables include general findings (normal/ abnormal, 
not clinically significant/ abnormal, clinically significant). The cause of any clinically 
significant ECG will be specified.

Laboratory test results: biochemistry, hematology, coagulation, and urinalysis

Plasma citrulline levels

Presence of antibodies to teduglutide and titer level, if present

Gastrointestinal imaging/testing (upper GI series with small bowel follow-through 
[UGI/SBFT], abdominal ultrasound, colonoscopy or sigmoidoscopy, fecal occult blood)
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
Pregnancy testing for females of childbearing potential

Nutritional support prescriptions (eg, PN/IV and enteral nutrition [EN] volume and calories, 
PN/IV hours per day and days per week) (Section 7.2.15.2)

Nutritional support diary data (Section 7.2.15.3)
7.2.5
Pharmacokinetic Assessments
Pharmacokinetic assessments are listed in Section 9.10.1. 
Blood samples for teduglutide concentrations will be collected at the baseline and week 4 visits. 
If blood samples are not/cannot be collected at week 4, the uncollected samples can be collected
during any future site visit while the subject is still on investigational product. A schedule of PK 
sample collection is provided in Table 4. Instructions for sample collection and handling are 
included in the Laboratory Manual.
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing
Study week
Baseline
Week 4
Visit Number
2
6
Hour
0a
1
6
0a
2
4
a Prior to investigational product administration
The timepoints indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these timepoints may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

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 (at the week 4 draw).

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes

6-hour postdose draw: ±30 minutes
At PK timepoints, the date and time of investigational product administration and blood 
collection must be recorded on the eCRF.
7.2.6
Physical Examination (Including Height and Weight)
Physical examinations will be performed, and body weight, height (or length), and head 
circumference (up to 36 months of age) measured according to the Study Schedules.
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Physical examinations will be performed by the investigator during the study 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.
Subjects should be weighed on the same scale at each study visit. Height (or length [cm]) and 
head circumference (for subjects ≤36 months of age[cm]) will be measured at selected visits.
Body mass index (BMI) and z-scores for weight, height (or length), head circumference, and 
BMI will be calculated by the sponsor. 
7.2.7
Vital Signs
Vital signs will be measured according to the Study Schedules. Measurements will include body 
temperature (°C), heart rate (beats per minute), and systolic and diastolic blood pressure 
(mmHg). 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.
7.2.8
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing according to the Study Schedules. Subjects should be in a seated or supine position during 
blood collection.
Laboratory collections required at intervals that do not coincide with site visits (safety laboratory
assessments eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at 
the investigational site. 
Clinical laboratory tests will include the following (see Table 5):
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Table 5
List of Laboratory Tests
Hematology:
Hematocrit 
Hemoglobin 
Platelet count
Red blood cell (RBC) count 
RBC morphology, if needed
White blood cell count with differential
Coagulation:
Prothrombin time/International  normalized ratio 
will be measured in all subjects at screening and 
subsequently if confirmed drug-induced liver 
injury (DILI) is suspected (Section 8.4.2)
Urinalysis: 
Blood
Glucose
Leucocytes
Microscopic analysis
pH and osmolality
Protein
Sodium
Specific gravity
Pregnancy tests (females of childbearing potential):
Serum β-HCG (screening)
Urine β-HCG (all other visits)
Biochemistry:
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
C-reactive protein 
Creatinine
Estimated glomerular filtration rate 
(Schwartz formula)
Gamma-glutamyl transferase 
Glucose
Lipase
Magnesium
Phosphorus
Potassium 
Sodium 
Triglycerides
Uric acid
For children in diapers, urine specimen collection should be attempted as part of the safety lab
assessments, but lack of urinalysis will not constitute a protocol deviation.
7.2.9
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass. Blood samples will
be collected 2 to 4 hours postprandial, whenever possible, at the timepoints specified in the 
Study Schedules. Samples may be drawn from a central line or peripheral access and processed 
according to instructions in the Laboratory Manual. 
7.2.10
Antibody Assessments
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the baseline visit (day 0) and at least 14 hours after the previous 
dose at the EOT visit (week 24 or early termination); samples may be drawn from a central line 
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or peripheral access. One additional sample will be collected at the EOS 4 weeks after the EOT 
(ie, week 28 or EOS). 
If a blood sample tests positive for anti-teduglutide antibodies at week 28 or EOS, then the 
subject will be retested 3 months after EOT. If that sample tests positive, then the subject will be 
retested 6 months after EOT.
7.2.11
Pregnancy Testing
Any female subject of childbearing potential (Section 4.3) must have negative pregnancy tests to 
enroll or continue in the study. Pregnancy tests will be performed at screening (serum β-HCG 
testing) and at all site visits (urine β-HCG testing). 
7.2.12
Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study.
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than one blood assessment 
is to be done at the same timepoint, the assessments should be combined if they require the same 
type of tube.
7.2.13
Electrocardiogram
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) 
as indicated in the Study Schedules. Electrocardiogram recordings will be read locally by an 
experienced physician. Results (normal; abnormal, not clinically significant; and abnormal,
clinically significant with a description of the abnormality) will be recorded on the eCRF. 
7.2.14
Gastrointestinal-specific Testing
Gastrointestinal testing will be performed as needed for all subjects during the screening period, 
as indicated in sections 7.2.14.1 to 7.2.14.4. Follow-up testing will be performed as needed
according to the guidelines noted in sections 7.2.14.1 to 7.2.14.4 and the Study Schedules.
7.2.14.1
Upper Gastrointestinal Series with Contrast
An UGI/SBFT will be performed following the ingestion of barium contrast material during the 
screening period. Results from procedures performed within 6 months prior to visit 1 will also be 
acceptable.
7.2.14.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to visit 1 will also be acceptable.
7.2.14.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, week 12, and week 24 (EOT). 
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Subjects with positive fecal occult blood testing results at screening or at week 24 for whom a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy. Subjects with positive fecal occult blood testing results at week 12 for which a 
cause is not identified by a physical examination will be discussed with the Shire medical 
monitor or designee. If clinically indicated, an esophagogastroduodenoscopy (EGD) may also be 
performed with any colonoscopy or sigmoidoscopy.
Subjects with negative endoscopy findings at screening may enroll in the study.
Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with Shire’s medical monitor or designee, the subject is 
considered appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with Shire’s medical monitor or designee, the 
subject is considered inappropriate to be enrolled in the study.
7.2.14.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy or sigmoidoscopy at screening. 
If the fecal occult blood testing is negative at screening and the procedure was performed within 
1 year before the screening visit (visit 1), then those prior results are acceptable for the screening 
assessment.
Children younger than 12 years will undergo the procedure if they test positive for fecal occult 
blood at screening and the cause is not identified by physical examination (see Section 7.2.14.3).
Requirements for colonoscopy or sigmoidoscopy in response to positive fecal occult blood 
testing at weeks 12 or 24 are presented in Section 7.2.14.3.
7.2.15
Other Study Procedures
7.2.15.1
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/legally-
authorized representative in a GI-specific symptoms history diary on a daily basis. At the 
baseline visit, the investigator will review the GI-symptoms diary and summarize the findings.
7.2.15.2
Nutritional Support
Nutritional support includes PN/IV and EN. Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status,
and safety laboratory results. Guidelines for nutritional support management and weaning 
algorithms are provided in Appendix 2 and Appendix 3, respectively.
Intake diaries will be used to collect and evaluate each subject’s nutritional support.
7.2.15.3
Diaries
The subject/parent/legally-authorized representative will complete the appropriate fields of the 
PN/IV and EN (formula) sections of the intake diary.
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Intake diary:  The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:
PN/IV volume and infusion duration
EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
Output diary:  Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every site visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc. The subject or parent will 
perform dipstick specific gravity tests on the first urine produced after the daily 
infusions of PN/IV support.

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first 
void after the daily PN/IV infusion to measure specific gravity.

Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency 
using the Bristol Stool Form Scale (see output diary)

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine 
and stool) as stool output and score the stool consistency using the Bristol Stool 
Form Scale (see output diary). Stool volume will be calculated using the formula:
1 g (scale weight) = 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
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8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 3.2. This includes events occurring during the screening phase 
of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Note that the severity of AEs listed in Table 6 that may lead to dose interruption based on known 
risks of teduglutide will also be evaluated using the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria (Section 8.4.1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
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, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the 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 end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment 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, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 3.2.
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 SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol. Note: An
elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol as well as the Shire 
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Investigational and Marketed Products Pregnancy Report Form. The test date of the first positive 
serum/urine β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Administration of a dose greater than the allocated dose of investigational 
product or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event. Note: The 24-hour 
reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors (see Section 8.1.7) unless they result in an SAE. 
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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 
e-mail address can be found on the form (sent under separate cover). 
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed 
consent/assent is signed until the defined follow-up period stated in Section 3.2 and must be 
reported to Quintiles Transnational Japan K.K 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 Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event.
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8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent form, or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
Quintiles Transnational Japan K.K is responsible for notifying the relevant regulatory 
authorities/central institutional review boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs. In addition the sponsor and/or designee is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the
teduglutide program. 
The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system
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
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, Quintiles Transnational Japan K.K Quintiles Transnational Japan 
K.K must be informed within 24 hours of first awareness as per the SAE notification instructions 
described in Section 8.2.2 even if the event does not fulfill seriousness criterion.
8.4
Dose Interruption of Individual Subjects 
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
Investigational product must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related to 
the investigational product. This does not include the presence of anti-teduglutide antibodies, 
mild injection site reactions or mild symptoms that according to the investigator do not pose
a significant risk to the subject.

An AE listed in Table 6 that is of NCI CTCAE severity Grade 3 or 4 and considered to be 
related to the investigational product administration (see Section 8.4.1)

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The investigational product may be discontinued if the subject experiences an AE listed in Table 
6 that is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with 
Shire’s medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the DMC should be guided by the descriptions of Grade 3 and 4 events, as they 
relate to identified risks associated with the administration of teduglutide (see Table 6).
Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent
intervention indicated
Intestinal obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening  consequences; urgent
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or
hospitalization indicated; nonemergent
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (total bilirubin >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification laboratory assessments and an 
inquiry should be made as to the presence of clinical symptoms consistent with new liver injury. 
The subject should be followed closely to determine the trajectory of the laboratory 
abnormalities and to evaluate the cause of liver injury. This evaluation may include, as clinically 
indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A immunoglobulin M [IgM], 
hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, Epstein-Barr virus
antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (anti-nuclear, anti-
smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), intestinal failure 
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associated liver disease, cardiovascular causes such as ischemic hepatitis, and concomitant 
hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with Shire medical monitor or designee.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
investigational product.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

At least 2 subjects develop the same event listed in Table 6 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 6 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying disease 
process.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator or investigators’ authorized site personnel must enter the information required 
by the protocol in the eCRF. A study monitor will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the eCRF will be addressed by 
the investigator or qualified site personnel. When a data discrepancy warrants correction, the 
correction will be made by the investigator or authorized site personnel. The investigator must 
verify that all data entries in the eCRF are accurate and correct. Original diary data should be
entered into the eCRF and take precedence over data collected over the phone. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. Once a subject is enrolled, it is expected that the investigator or authorized site 
personnel will complete the eCRF entry in a timely manner following the subject’s visit.
9.2
Clinical Data Management
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US Food and Drug Administration (FDA) 21 CFR Part 11 Guidance. The 
clinical trial database will include an audit trail to document any evidence of data processing or 
activity on each data field by each user. 
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Pharmacovigilance and Risk Management database.
9.3
Statistical Analysis Process
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.
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Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
All statistical analyses will be performed using SAS®.
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design.
9.4.1
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by Shire, independent contractors hired by Shire, or members of regulatory 
agencies. The DMC may make recommendations to Shire regarding stopping, modifying or 
continuing the study; however, Shire will have the final responsibility to determine whether the 
study should be modified or temporarily or permanently stopped. 
Safety and tolerability results will be evaluated by a DMC which will convene approximately 
every 3 months during the active study period (date of the first subject’s first dose to date of the 
last subject’s last dose), based on subject enrollment. The DMC review will include all 
cumulative safety data from study assessment through the end of each review period.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation.
9.6
Study Population
Subjects are considered enrolled in the study when they meet all eligibility criteria at screening 
and eligibility criteria are confirmed at visit 2/baseline.
The ITT population is defined as any subjects who were enrolled into the study. The safety 
population is defined as the subset of ITT with subjects who received at least 1 administration of 
investigational product with any safety follow-up. The primary population analyzed for 
efficacy/PD will be the ITT population. An additional per-protocol population analysis will also 
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be performed as secondary/sensitivity analysis. The per-protocol population is defined as the 
subset of subjects in the ITT population without a major protocol deviation. Details will be 
prospectively defined in the final SAP prior to database lock.
The PK analysis population is defined as all subjects in the safety analysis population for whom 
the primary PK data are considered sufficient and interpretable.
9.7
Demographics and Baseline Characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories) will be presented, as appropriate, to 
summarize the demographic and baseline variables.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized. 
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with specific histories 
will be summarized by system organ class and preferred term.
9.8
Efficacy/Pharmacodynamic Analyses
The efficacy/PD endpoints include:

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) 
compared to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, to 
week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
No formal statistical test will be performed due the limited sample size.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
9.9
Safety Analyses
The safety and tolerability variables include:
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
Adverse events, including those pertaining to GI symptoms

Body weight, height (or length), head circumference (up to 36 months of age), and trends on 
growth charts

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis) including the 
following lab tests at all site visits and interim safety labs to detect hepatoxicity signals:  
AST, ALT, ALP, and bilirubin

Urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal 
occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment-emergent AEs will be summarized by 
system organ class and preferred term. The number and percentage of subjects with AEs, SAEs, 
AEs that lead to discontinuation, investigational product-related AEs (determined by the 
investigator), and AEs that resulted in a fatal outcome will be summarized. AEs will also be 
summarized with regard to intensity and relationship to investigational product. For AEs of 
special interest, the CTCAE grading system will be used as described in Section 8.4.1.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies.
9.10
Other Analyses
9.10.1
Pharmacokinetic Analyses
The following PK parameters will be estimated based on measured teduglutide plasma 
concentrations using a population PK modeling approach:

Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)

AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Cmax at steady state (Cmax,ss)
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
Minimum plasma concentration at steady state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics for PK parameters (mean, median, standard deviation, minimum and 
maximum values, geometric mean) will be calculated.
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10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee ensures that local regulatory authority requirements are met before the 
start of the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior to 
release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor or designee is responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries may include participating 
investigators’ names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
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10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor or designee before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent/assent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable contract research 
organization, investigator, or for multicenter studies, the coordinating principal investigator 
according to national provisions and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms will be supplied by the sponsor or designee and should be handled 
in accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
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must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded solely onto the eCRF.
All data transmitted to the sponsor or designee must be endorsed by the investigator. The study 
monitor will verify the contents against the source data per the monitoring plan. If the data are 
unclear or contradictory, queries will be sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to subject’s 
medical file, subject diaries, and original clinical laboratory reports, and imaging reports. All key 
data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays, etc). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the 
Pharmaceuticals and Medical Devices Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator receives from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator or designee to obtain written informed consent from all 
subjects or parents/legally-authorized representatives, and assent from subjects where applicable, 
prior to any study-related procedures including screening assessments. All consent and assent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s parent or legally-authorized representative, as applicable, is requested to sign and date 
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the informed consent form/assent, or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed 
consent/assent documentation (ie, a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s parent or legally-authorized 
representative, as applicable. This document requires translation into the local language. Signed 
consent/assent forms must remain in each subject’s study file and must be available for 
verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form and assent 
form where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent
document (approved by the sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. Responsibility for coordinating with IRBs/ECs is defined in the 
investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor or designee has received 
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies 
this can be done by the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
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.
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After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) 
which gave approval for the study to proceed. The sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. 
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 
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submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11
LIST OF REFERENCES
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Kitajima, M., Shamizu, M., Wakabayashi, G., Hoshino, K., Tanabe, M. & Kawachi, S. 2013. 
Current Issues in Liver and Small Bowel Transplantation, Springer Science & Business 
Media.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D., Boctor, D., Brindle, M., Lam, V. & Robertson, M. 2011. Elements of successful 
intestinal rehabilitation. J Pediatr Surg, 46, 150-6.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Takagi, Y., Okada, A., Sato, T., Fukushima, T., Shirotani, N., Osawa, Y., Takeyama, H., 
Taniguchi, M., Takehara, H. & Mizote, H. 1995. Report on the first annual survey of 
home parenteral nutrition in Japan. Surg Today, 25, 193-201.
Takehara, H. 2001. Home parenteral nutrition for pediatric patients. Nihon Rinsho, 59 Suppl 5,
848-51.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
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12
APPENDICES
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
18 Dec 2015
Global
Amendment 1
27 Apr 2016
Global
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Appendix 2
Guidelines for Nutritional Support Management During the Study
(SHP633-302)
Nutritional support adjustment in volume and calories should be considered at all planned visits.
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should be considered for managing nutritional support 
(PN/IV and EN [PN/EN]) in terms of volume and calories during the treatment period:

Growth trajectory, including weight, height (or length), and head circumference (for children 
up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen/creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Form Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food and fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.
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Appendix 3
Weaning Algorithms  
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in Diapers
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Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers
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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment
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CLINICAL TRIAL PROTOCOL: SHP633-302
TITLE:
A 24-week Safety, Efficacy, Pharmacodynamic, and 
Pharmacokinetic Study of Teduglutide in Japanese Pediatric 
Subjects, Aged 1 Year through 15 Years, with Short Bowel 
Syndrome who are Dependent on Parenteral Support
NUMBER:
SHP633-302
PHASE:
3
DRUG:
Teduglutide 
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421 USA
PROTOCOL 
HISTORY:
Amendment 2: 06 Jun 2017
Amendment 1: 27 Apr 2016
Original Protocol: 18 Dec 2015
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
Date: 
 
, MD, PhD 
, Global Clim""""'...LU....,elopment 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-302. 
Title: A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 1 Year through 15 Years, 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 or subject's legally-authorized representative in 
order to obtain their consent/assent to participate. 
I agree to conduct this study according to this protocol and to comply with its 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
r 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 r will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and 
Address: 
(please hand print or type) 
Signature: 
Date: 
Shire 
CONFIDENTIAL 
Page 2 
Protocol SHP633-302 
 
06 Jun 2017 
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
06 Jun 2017
Global
Description of Change
Section(s) Affected by Change
The Pharmacovigilance SAE Reporting fax number and email address have 
been updated. A sentence has been removed from the emergency contact 
information to eliminate a redundancy with the information provided under 
the Pharmacovigilance SAE Reporting heading (Protocol Administrative 
Change Memo #2, dated 24 Aug 2016). The title of Andrew Grimm MD 
PhD is now Medical Director and his email address has been changed.
Protocol Signature Page
Emergency Contact Information
Urine osmolality (Protocol Administrative Change Memo #1, dated 10 Aug 
2016) and urine sodium have been removed from the list of urinalysis 
parameters to be tested. Neither parameters are needed as safety parameters
nor required for the decision to adjust a subject’s nutritional support.
Table 5
Clarification that biological therapy prohibited during teduglutide treatment 
and within 6 months prior to the pretreatment visit refers to biological 
therapy used to treat inflammatory bowel disease.
Section 5.3
Clarification that subjects, and/or any designated person who will be 
administering the investigational product, will be trained on investigational 
product preparation and administration before the first dose of teduglutide 
or the implementation of any change in ancillary kit components.
Section 6.2
Language on contents of ancillary kits has been revised.
Section 6.3.1
See Appendix 1 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event, the investigator must fax or e-mail the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to Quintiles Transnational Japan K.K using the details 
below. 
In-country Clinical Caretaker:
 
, 
: 
Quintiles Transnational Japan K.K
Phone: 
Email:
Fax:
Pharmacovigilance SAE Reporting:
FAX: 
 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 between 8:00 to 20:00 US Eastern Standard 
Time, the investigator may contact the Shire medical monitor:
, MD, PhD
, Global Clinical Development
Office Phone: 
Mobile Phone: 
Email:
Fax: 
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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 adverse events related to product complaints, see 
Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed):
Shire (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF IN-TEXT TABLES ........................................................................................................10
LIST OF IN-TEXT FIGURES.......................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES..................................................................................................................17
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background and Clinical Information ........................................................22
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Clinical Study...............................................................................25
2.2
Objective(s) ..............................................................................................................25
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................31
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Subject Withdrawal Criteria ..................................................................................31
4.4.2
Reasons for Discontinuation..................................................................................31
4.4.3
Subjects “Lost to follow-up” Prior to Last Scheduled Visit..................................32
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.1
Prior Treatment ........................................................................................................33
5.2
Concomitant Treatment............................................................................................33
5.3
Prohibited Treatment................................................................................................33
6
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Blinding of the Treatment Assignment..................................................................34
6.2
Administration of Investigational Product ...............................................................34
6.2.1
Allocation of Subjects to Treatment ......................................................................35
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6.3
Labeling, Packaging, and Storage............................................................................35
6.3.1
Labeling and Packaging.........................................................................................35
6.3.2
Storage ...................................................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Treatment Compliance .............................................................................................37
7
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Treatment Period....................................................................................................38
7.1.3
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Informed Consent...................................................................................................38
7.2.2
Study Entrance Criteria..........................................................................................39
7.2.3
Confirmation of Study Eligibility..........................................................................39
7.2.4
Demographics and Other Baseline Characteristics................................................39
7.2.5
Pharmacokinetic Assessments ...............................................................................40
7.2.6
Physical Examination (Including Height and Weight)..........................................40
7.2.7
Vital Signs..............................................................................................................41
7.2.8
Clinical Laboratory Tests.......................................................................................41
7.2.9
Plasma Citrulline....................................................................................................42
7.2.10 Antibody Assessments...........................................................................................42
7.2.11 Pregnancy Testing..................................................................................................42
7.2.12 Volume of Blood....................................................................................................43
7.2.13 Electrocardiogram..................................................................................................43
7.2.14 Gastrointestinal-specific Testing ...........................................................................43
7.2.14.1
Upper Gastrointestinal Series with Contrast ..........................................43
7.2.14.2
Abdominal Ultrasound ...........................................................................43
7.2.14.3
Fecal Occult Blood Testing....................................................................43
7.2.14.4
Colonoscopy/Sigmoidoscopy.................................................................44
7.2.15 Other Study Procedures .........................................................................................44
7.2.15.1
GI-specific Symptoms History...............................................................44
7.2.15.2
Nutritional Support.................................................................................44
7.2.15.3
Diaries ....................................................................................................44
8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ....................................46
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..........................................................................................46
8.1.2
Relationship Categorization...................................................................................47
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8.1.3
Outcome Categorization ........................................................................................47
8.1.4
Symptoms of the Disease Under Study .................................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................48
8.1.6
Pregnancy...............................................................................................................48
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................49
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information................................................................................49
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................50
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................51
8.2.6
Fatal Outcome........................................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................51
8.3
Adverse Events of Special Interest...........................................................................51
8.4
Dose Interruption of Individual Subjects .................................................................52
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide.......................52
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury...........................54
8.5
Early Termination of the Clinical Study ..................................................................55
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................56
9.1
Data Collection.........................................................................................................56
9.2
Clinical Data Management.......................................................................................56
9.3
Statistical Analysis Process......................................................................................56
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......57
9.4.1
Data Monitoring Committee..................................................................................57
9.5
Sample Size Calculation and Power Considerations................................................57
9.6
Study Population ......................................................................................................57
9.7
Demographics and Baseline Characteristics ............................................................58
9.8
Efficacy/Pharmacodynamic Analyses......................................................................58
9.9
Safety Analyses........................................................................................................59
9.10
Other Analyses .........................................................................................................59
9.10.1 Pharmacokinetic Analyses.....................................................................................59
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................61
10.1
Sponsor’s Responsibilities .......................................................................................61
10.1.1 Good Clinical Practice Compliance.......................................................................61
10.1.2 Public Posting of Study Information......................................................................61
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................61
10.1.4 Study Suspension, Termination, and Completion..................................................61
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10.2
Investigator’s Responsibilities .................................................................................62
10.2.1 Good Clinical Practice Compliance.......................................................................62
10.2.2 Protocol Adherence and Investigator Agreement..................................................62
10.2.3 Documentation and Retention of Records.............................................................62
10.2.3.1
Case Report Forms.................................................................................62
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................63
10.2.3.3
Financial Disclosure...............................................................................63
10.3
Ethical Considerations..............................................................................................63
10.3.1 Informed Consent...................................................................................................63
10.3.2 Institutional Review Board or Ethics Committee..................................................64
10.4
Privacy and Confidentiality......................................................................................65
10.5
Study Results/Publication Policy .............................................................................65
11 LIST OF REFERENCES........................................................................................................67
12 APPENDICES ........................................................................................................................68
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LIST OF IN-TEXT TABLES
Table 1
Study Schedule of Events – Screening to Week 12...................................17
Table 2 
Study Schedule of Events  – Weeks 13 to 28 ............................................20
Table 3
Examples of Excluded Diseases and Illnesses...........................................30
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing.............40
Table 5
List of Laboratory Tests.............................................................................41
Table 6
Adverse Events that May Lead to Dose Interruption.................................53
LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram ...........................................................................................27
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in 
Diapers .......................................................................................................73
Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers................................74
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment.......................75
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-inf
AUC of zero to infinity
AUC0-t
AUC from zero to the last measurable concentration
AUCss
AUC at steady state
BMI
body mass index
Cmax
maximum plasma concentration
Cmax,ss
Cmax at steady state
Cmin, ss
minimum plasma concentration at steady state
CL/F
apparent clearance
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EC
ethics committee
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
US Food and Drug Administration
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GCP
Good Clinical Practice
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
IgM
immunoglobulin M
INR
international  normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
NCI
National Cancer Institute
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
PN/EN
parenteral nutrition/ intravenous fluids and enteral nutrition
PN/IV
parenteral nutrition/intravenous fluids
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow-through
ULN
upper limit of normal
US
United States
Vλz/F
apparent volume of distribution
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STUDY SYNOPSIS
Protocol number: SHP633-302
Drug: Teduglutide
Study Title:
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of Teduglutide in Japanese 
Pediatric Subjects, Aged 1 Year through 15 Years, with Short Bowel Syndrome who are Dependent on 
Parenteral Support
Number of subjects: 
Planned enrollment is approximately 5 subjects.
Sites and Regions: Approximately 5 investigational sites in Japan are planned.
Study Duration:
There will be, at a minimum, a 2-week screening period followed by 24 weeks of   treatment. The end of 
study (EOS) visit will be scheduled at week 28, 4 weeks after the end of treatment (EOT) visit (week 24).
Investigational Product, Dose, and Mode of Administration: 
During the treatment period, a dose of 0.05 mg/kg/day of teduglutide will be administered once daily
subcutaneously (SC) to the subjects. The dose calculation will be based on body weight measured at the 
baseline visit (visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with Shire medical monitor or designee.
Objective(s): 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and pharmacodynamics 
(PD), and pharmacokinetics (PK) of teduglutide in pediatric subjects (1 year through 15 years of age) with 
short bowel syndrome (SBS) who are dependent on parenteral support. 
Study Design:
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of teduglutide. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the requirements 
for nutritional support for each subject and to ensure adherence to eligibility parameters. Attempts should be 
made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the first 2 weeks 
(weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, and 12). For the remainder 
of the treatment period, visits at the sites will be conducted every 3 weeks (at weeks 15, 18, 21, and 24). 
Scheduled telephone contacts will be made on all other weeks during the treatment period. At all site visits 
and during telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. The EOS visit will be scheduled at week 28, 4 weeks following EOT. Weekly telephone 
contact will be made during the interim weeks from EOT to EOS to monitor safety and any changes in 
nutritional support.
To maintain consistency across all centers, all attempts should be made to follow the nutritional support 
adjustment guidelines and weaning algorithms (developed with SBS expert input and to be provided in the 
protocol) for decisions regarding parenteral nutrition/intravenous fluids (PN/IV) support reduction and 
advances in enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
Any departure from the nutritional support adjustment guidelines and weaning algorithms will not constitute 
a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have positive/specific 
antibodies, they will be asked to return for a follow-up visit 3 months post EOT for another antibody 
sample. If the subjects continue to have positive/specific antibodies at 3 months post EOT, they will be 
asked to return for follow-up visit(s) up to 6 months post-treatment in order to determine their antibody 
status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee periodically during the 
active study period, based on subject enrollment.
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All subjects who complete the study may participate in a long term extension study in which eligible 
subjects could receive teduglutide.
Study Inclusion and Exclusion Criteria:
Subjects who satisfy the following inclusion and exclusion criteria will be enrolled in the study. 
Inclusion Criteria 
1.
Informed consent by a parent or legally-authorized representative prior to any study-related procedures
2.
When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the 
subject prior to any study-related procedures 
3.
Male or female child or adolescent aged 1 year through 15 years
4.
Current history of SBS as a result of major intestinal resection (eg, due to necrotizing enterocolitis, 
midgut volvulus, intestinal atresia, or gastroschisis)
5.
Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or 
fluid/electrolyte needs
6.
Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually associated 
with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at 
least 3 months prior to and during screening, as assessed by the investigator. Transient instability for 
events such as interruption of central access or treatment of sepsis is allowed if the PN/IV support 
returns to within 10% of baseline prior to the event.
7.
Sexually active female subjects of childbearing potential must use medically acceptable methods of 
birth control during and for 4 weeks following the last dose of investigational product
Exclusion Criteria
1.
Subjects who are not expected to be able to advance oral or tube feeding regimens 
2.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of 
screening 
3.
Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and 
inability to reduce parenteral support 
4.
Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5.
Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
6.
Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done within 6 months 
prior to screening
7.
Major GI surgical intervention including significant intestinal resection within 3 months prior to 
screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections ≤ 10 cm, or 
endoscopic procedure is allowed)
8.
Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation 
9.
History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous 
basal or squamous cell carcinoma, or in situ non-aggressive and surgically resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 
3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to screening and for the 
duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to 
screening
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14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to 
screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, antitumor 
necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant 
therapy that had been introduced or changed during the 3 months prior to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-related catheter 
sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the 
screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements within 1 
month prior to or during screening, excluding uncomplicated treatment of bacteremia, central line 
replacement/repair, or issues of similar magnitude in an otherwise stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the screening
period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d.
Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results 
of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of understanding or 
not willing to adhere to the study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results. Examples 
of potential disease states/illnesses that may be excluded are listed in Table 3.
Pharmacokinetic Variables:
Blood samples for drug concentrations will be collected at the baseline visit (predose, at 1 and 6 hours 
postdose) and at week 4 visit (predose, 2 and 4 hours postdose). If blood samples are not/cannot be collected 
at week 4, the uncollected samples can be collected during any future site visit while the subject is still on 
investigational product. 
The following PK parameters will be derived using a population PK modeling approach:

Area under the plasma concentration–time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)

Area under the concentration-time curve at steady-state (AUCss)

Maximum plasma concentration (Cmax)

Maximum plasma concentration at steady-state (Cmax,ss)

Minimum plasma concentration at steady-state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
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Efficacy/Pharmacodynamic Assessments:
The efficacy/PD endpoints include:

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), citrulline, 
and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) compared 
to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
Safety Assessments:
Safety and tolerability will be assessed by evaluating the following: 

Adverse events, including those pertaining to GI symptoms. 

Physical examinations, including body weight, height (or length), head circumference (up to 36 months 
of age), and trends on growth charts

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms (ECGs)

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)  

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal occult blood 
testing, upper GI series with small bowel follow-through
Safety and tolerability will be evaluated by a Data Monitoring Committee during the study period.
Statistical Methods:
Due to the limited size of the study population, descriptive statistics will be used with a goal of summarizing 
the sample. As such, no claims of significance will be made for any of the data. 
Pharmacokinetic parameters will be estimated based on measured teduglutide plasma concentrations using a 
population PK modeling approach.
Continuous variables will be summarized using descriptive statistics including number of subjects, mean, 
median, standard deviation, maximum, and minimum. For categorical variables, statistical summaries will 
include number of subjects and percentages.
Efficacy/PD data will include change in PN/IV support, enteral nutritional support, plasma citrulline, and 
hours per day and days per week of PN/IV support, and will be summarized by visit.
Safety data will include clinical laboratory tests results; measurement of body weight, height (or length), and 
head circumferences (if applicable); vital signs; concomitant medications; and ECG monitoring; and will be 
summarized by visit. Adverse events will also be collected and summarized. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from baseline, if applicable. Frequency 
counts will be compiled for classification of qualitative safety data.
Date of Original Protocol: 18 Dec 2015
Date of Most Recent Protocol Amendment (if applicable): 27 Apr 2016
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STUDY SCHEDULES
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Informed 
consent/assenta
X
Eligibility
X
X
Demographics 
X
Medical /surgical 
history
X
Electrocardiogram
X
X
SBS history
X
Upper GI with small 
bowel follow-through
and abdominal 
ultrasoundb
X
Fecal occult blood 
testingc
X
X
Colonoscopy/ 
sigmoidoscopyc
(X)
(X)
Provide GI-specific 
symptoms history diary
X
Review GI-specific 
symptoms history diary
X
Dispense 
investigational productd
X
X
X
X
X
X
X
X
Pharmacokinetic 
sampling
Xe
Xf
Safety laboratory testsg
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testingh
X
X
X
X
X
X
X
X
X
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Plasma citrullinei
X
X
Antibodies to 
teduglutidej
X
Provide intake and 
output diaries
X
X
X
X
X
X
X
X
X
Review diaries and 
nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Physical examination/ 
vital signs/weight
X
X
X
X
X
X
X
X
X
Height (or length) and 
head circumferencem
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PK=pharmacokinetic; PT/INR=prothrombin time/international normalized ratio; 
PN/IV=parenteral nutrition/intravenous fluids; SBS=short bowel syndrome; SC=subcutaneous; UGI/SBFT= upper GI series with small bowel follow through
a
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b
If the subject has undergone an UGI/SBFT and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable for the 
screening assessments. If the subject has not had these procedures within the 6 months before visit 1 (screening), then the procedure(s) will be performed any time after 
providing informed consent with the results available and reviewed before the baseline visit (day 0).
c
All subjects enrolled will have a fecal occult blood test after providing consent/assent. Subjects with positive fecal occult blood test at screening for whom a readily 
detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or sigmoidoscopy. Colonoscopy or sigmoidoscopy will be conducted at screening on all 
subjects 12 years of age and older; however if the screening fecal occult blood test is negative and the subject has undergone the procedure within 1 year before visit 1 
(screening), then that result will be acceptable for the screening assessment (Section 7.2.14.4). Subjects with positive fecal occult blood test results at week 12 for which a 
cause is not identified by a physical exam will be discussed with the Shire medical monitor or designee (Section 7.2.14.3).
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
10
Week 
11
Week
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
d
The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at 
least 4 hours. The site of administration (arm, thigh, abdomen) must be specified and recorded in the eCRF. The dose of study medication may be adjusted at week 12.
e
Baseline (visit 2) samples for PK analysis will be drawn predose, and 1 and 6 hours postdose (Section 7.2.5).
f
Week 4 (visit 6) samples for PK analysis will be drawn predose, and 2 and 4 hours postdose (Section 7.2.5).
g
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits (eg, 
biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine testing thereafter.  
i
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
j
Blood sample for antibody testing is to be collected at study site prior to first investigational product administration. Blood samples may be drawn from a central line or 
peripheral access (Section 7.2.10).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
m
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6).
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)
a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Dispense investigational 
product
X
X
X
Provide intake and output 
diaries
X
X
X
X
Review diaries and 
nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testsd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Pregnancy testinge
X
X
X
X
X
Plasma citrullinef
X
X
Antibodies to teduglutideg
X
X
Physical examination/
vital signs/weight
X
X
X
X
X
Height (or length) and 
head circumferenceh
X
X
X
X
X
Fecal occult blood testingi
X
Colonoscopy/ 
sigmoidoscopyi
(X)
Electrocardiogram
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or 
EOT/ET)
a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Concomitant medication/
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PN/IV=parenteral nutrition/intravenous fluid
a
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
d
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits 
(eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy (urine testing). 
f
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
g
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, at least 14 hours after the previous dose of teduglutide. If a blood sample is positive for 
antibodies at week 28 or EOS, then the subject will be retested 3 months after EOT. If that sample is positive, then the subject will be retested 6 months after EOT. 
h
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
i
Subjects with positive fecal occult blood test at week 24 (EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory 
colonoscopy or sigmoidoscopy (Section 7.2.14.3).
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease that results in major surgical resections of the small intestine. In children, most 
cases of short bowel syndrome begin in infancy. Common causes of SBS in children include 
necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. (Duro et al. 2008;
Squires et al. 2012) Similar to adults, new-onset SBS in older children usually stems from 
Crohn’s disease, trauma, and cancer. The diminished absorptive capacity for fluids and nutrients 
often results in dependence on parenteral nutrition or intravenous fluids (PN/IV) to maintain 
energy and fluid and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus height 
and crypt depth, dilation, and delayed intestinal transit. The main principle of management of 
SBS is to provide the minimal necessary parenteral support to maintain energy, fluid, and
electrolyte homeostasis while maximizing enteral feeding to promote intestinal adaptation. In 
infants, rapid linear growth of the intestines during the first year of life dramatically 
complements the aforementioned adaptive responses. About 30% of infants who develop SBS 
during the neonatal period become independent of PN/IV requirements by 12 months of age, and 
an additional 10% wean off PN/IV support by 24 months of age. After this time, linear intestinal 
growth slows. About 60% of children with SBS are able to become independent of parenteral 
support within 5 years. (Khan et al. 2015; Squires et al. 2012) Nevertheless, despite optimal 
medical management, many children remain dependent on PN/IV support.
Complications of long-term parenteral support include liver disease, catheter-related blood 
stream infections, central line-associated venous thrombosis and dwindling central venous 
access. Sepsis is the leading cause of death in these patients, and quality of life is poor. 
Accelerating the adaptive process is an urgent goal for all patients with SBS who are dependent 
on parenteral support.
For this reason, research in the pediatric arena is focused on children with PN/IV-dependent 
SBS. Given intestinal adaption in younger children, the unmet medical need is the greatest in 
children who are 1 year of age and older. It is highly unlikely that children with less than 10% of 
the expected length of small intestine reach enteral independence. These subjects reach a plateau 
in their ability to advance oral/enteral feeds or decrease PN/IV support (ie, are “stuck”) and are 
not expected to achieve spontaneous adaptation. Subjects who have not progressed to full enteral 
adaptation by 12 months after their intestinal insults are very unlikely to demonstrate 
spontaneous improvement in their enteral function. (Sigalet et al. 2011)
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide-2 (GLP-2), which is secreted from L-type 
enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
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There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS. In the US and Europe, a GLP-2 analog called teduglutide is approved for the treatment 
of SBS in adult patients who are dependent on PN/IV support. 
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 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. (Thymann et al. 2014;
Tappenden et al. 2013)
Clinical Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries. Two 
completed adult studies (CL0600-004 and its extension, CL0600-005) evaluated safety and 
tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were dependent 
on parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, 
placebo-controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, 
assessed the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was 
a statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study. At week 24, the weekly reduction of PN/IV 
volume was similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, 
assessed the long-term safety of teduglutide and the proportion of responders in the CL0600-004 
study that maintained their response at the end of a further 28 weeks of treatment. The extension 
study also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in 
PN/IV. Seventy-five percent of the subjects who previously responded to teduglutide treatment 
in Study CL0600-004 maintained this response or experienced further improved benefit from 
teduglutide treatment. More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. Most of the adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus
13/43 subjects [30.2%], respectively). 
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This difference was clinically and statistically significant in both the intent-to-treat (ITT) 
(p=0.002) and per-protocol (p < 0.001) populations. Generally, the incidence of 
treatment-emergent AEs was distributed similarly across all treatment groups. The 
treatment-emergent AEs with a higher incidence in the teduglutide group were mainly of GI 
origin. A long-term, open-label extension study (CL0600-021) assessed safety and efficacy for 
up to 24 additional months (ie, up to 30 months of exposure for subjects who received 
teduglutide in Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in 
Study CL0600-020 and entered Study CL0600-021 completed a total of 30 months of treatment 
with teduglutide. Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral 
support resulting in a PN/IV volume reduction of 7.55 L/week, corresponding to a mean 
reduction of 65.6% relative to baseline prior to exposure to teduglutide at the beginning of 
Study CL0600-020. PN/IV use was reduced by at least 1 day per week in 21 of 30 subjects 
(70%) who completed 30 months of treatment. Of the 39 subjects who entered 
Study CL0600-021 after receiving placebo in Study CL0600-020, 29 completed 24 months of 
treatment with teduglutide. The mean reduction in PN/IV volume was 3.11 L/week from baseline 
at the start of Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support. Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support.
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU countries. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts. 
There were no deaths during the study and no treatment-emergent AEs related to teduglutide 
were reported. No discontinuations from study were due to AEs. 
Additional information is provided in the investigator’s brochure.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Clinical Study 
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014. 
Based on national surveys, it is estimated that the number of subjects with SBS who are 
dependent on parenteral nutrition/intravenous fluid (PN/IV) is less than 1000 in Japan.
(Takagi et al. 1995; Takehara 2001; Kitajima et al. 2013) Among the 195 SBS subjects in the 
2011 survey, 99 (51%) developed SBS at <1 years old. Early intervention could potentially 
improve intestinal adaptation and decrease the need for parenteral support in these patients.
The current study proposes to investigate the safe and appropriate use of teduglutide in the 
Japanese pediatric population for the purpose of providing pharmacokinetic, pharmacodynamic, 
and safety data. This protocol was developed similarly to the planned EU/US study, 
TED-C14-006, A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects through 17 Years of Age, with 
Short Bowel Syndrome who are Dependent on Parenteral Support. The TED-C14-006 protocol 
was developed with input from expert advisors from intestinal rehabilitation centers who offered 
advice on the most appropriate use of teduglutide in pediatric patients. The teduglutide dose of 
0.05 mg/kg daily is supported by results from the completed 12-week pediatric study. 
Teduglutide is approved for adult use in the US and EU at a dose of 0.05 mg/kg SC once daily. 
The completed 12-week pediatric study (TED-C13-003, A 12-Week Pharmacokinetic, Safety, 
and Pharmacodynamic Study of Teduglutide in Pediatric Subjects Aged 1 Year through 
17 Years, with Short Bowel Syndrome who are Dependent on Parenteral Support) demonstrated 
that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk 
profile. In addition, population pharmacokinetics (PK) modeling and simulations were conducted 
to determine the effective dose to be used in pediatric subjects using data from 8 adult clinical 
studies including adult Phases 1, 2, and 3 studies as well as the pediatric study (TED-C13-003);
they suggested that the dose in pediatric subjects is likely to be the same as the dose in adults.
(O'Keefe et al. 2006) The duration of teduglutide treatment in study SHP633-302 mirrors that of 
the TED-C14-006 study, consisting of 24 weeks of teduglutide treatment, followed by a 4-week 
follow-up period.
The aim of teduglutide treatment is to increase absorptive capacity in order to yield decreases in 
parenteral support. In addition, the experts anticipated that there would be several direct benefits 
from decreased parenteral support and advances in enteral feeds, including less exposure to 
PN/IV constituents, less central line manipulation with lower risk of infection, and more time to 
focus on oral rehabilitation strategies.
2.2
Objective(s) 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics (PD), and PK of teduglutide in pediatric subjects (1 year through 15 years of 
age) with SBS who are dependent on parenteral support. See Sections 9.8 and 9.10.1 for further 
details of the endpoints being measured, and Section 9.9 for safety variables.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of 
teduglutide. All subjects will be screened for a minimum of 2 weeks prior to start of treatment to 
verify the requirements for nutritional support for each subject and to ensure adherence to 
eligibility parameters. Attempts should be made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks (weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, 
and 12). For the remainder of the treatment period, visits at the sites will be conducted every 
3 weeks (at weeks 15, 18, 21, and 24). Scheduled telephone contacts will be made on all other 
weeks during the treatment period. At all site visits and during telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed. The end of study 
(EOS) visit will be scheduled at week 28, 4 weeks following end of treatment (EOT). Weekly 
telephone contact will be made during the interim weeks from EOT to EOS to monitor safety and 
any changes in nutritional support. The Study Schedules (Table 1 and Table 2) are displayed at 
the beginning of this protocol.
A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as 
an unscheduled visit.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines and weaning algorithms (developed with SBS expert input and 
provided in Appendix 2 and Appendix 3, respectively) for decisions regarding PN/IV support 
reduction and advances in enteral feeds based on weight gain, urine, and stool output in the 
setting of clinical stability. Any departure from the nutritional support adjustment guidelines and 
weaning algorithms will not constitute a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post EOT 
for another antibody sample. If the subjects continue to have positive/specific antibodies at 
3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) which 
will convene approximately every 3 months during the active study period, based on subject 
enrollment.
All subjects who complete the study may participate in a long term extension study in which 
eligible subjects could receive teduglutide.
A schematic representation of the study design is displayed in Figure 1.
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Figure 1
Study Diagram
EOS=end of study; EOT=end of treatment 
3.2
Study Duration
There will be, at a minimum, a 2-week screening period from the time of the screening visit to 
the baseline visit, followed by 24 weeks of treatment. Attempts should be made to limit the 
screening period to 4 weeks. The EOS visit will be scheduled at week 28, 4 weeks after the EOT 
visit (week 24). 
The start of the clinical phase is defined as first subject consented. The end of the clinical phase 
is defined as the last visit of the last subject.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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4
STUDY POPULATION 
Approximately 5 pediatric Japanese subjects, male and female children and adolescents aged 
1 year through 15 years, will be enrolled. 
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Informed consent by a parent or legally-authorized representative prior to any study-related 
procedures
2. When applicable, informed assent (as deemed appropriate by the Institutional Review Board) 
by the subject prior to any study-related procedures 
3. Male or female child or adolescent aged 1 year through 15 years 
4. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
5. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs
6. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment of sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
7. Sexually active female subjects of childbearing potential must use medically acceptable 
methods of birth control during and for 4 weeks following the last dose of investigational 
product
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
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7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease or congenital heart disease  or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic GLP-2 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
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22. Parent(s)/legally-authorized representative(s) and/or subjects who are not capable of 
understanding or not willing to adhere to the study visit schedule and other protocol 
requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results. Examples of potential disease states/illnesses that may be excluded are listed in 
Table 3.
Table 3
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in the GI tract 
identified by upper GI series, biopsy or polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug abuse within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease
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4.3
Reproductive Potential 
Sexually active females of childbearing potential must be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 4 weeks following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception if they become sexually active during the 
period of the study and 4 weeks following the last dose of investigational product. 
Female children and adolescent subjects should be either:
Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or
Females of childbearing potential with a negative serum β-HCG pregnancy test at the screening 
visit (visit 1) and a negative urine β-HCG pregnancy test prior to enrollment. Females of 
childbearing potential must agree to abstain from sexual activity (ie, true abstinence) that could 
result in pregnancy or agree to use medically acceptable methods of contraception at all times 
during the study and 4 weeks following the last dose of investigational product.
Note: True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).
4.4
Discontinuation of Subjects
4.4.1
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to further treatment. However, a discussion should be 
held by the investigator and the Shire medical monitor or designee prior to the subject
discontinuing or withdrawing. 
4.4.2
Reasons for Discontinuation

Reasons for discontinuation may include but are not limited to:

Adverse event

Death

Failure to meet enrollment criteria

Lost to follow-up

Non-compliance with investigational product

Physician decision

Pregnancy

Protocol deviation

Site terminated by sponsor
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
Study terminated by sponsor

Technical problems

Withdrawal by parent/legally-authorized representative

Withdrawal by subject
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 8.1. 
To the extent possible, all examinations scheduled for the EOT evaluation must be performed on 
all subjects who participate even if they do not complete the study according to the protocol
(ie, early termination). Any subject who discontinues treatment prematurely will be asked to 
return 4 weeks later for the EOS visit and will be contacted weekly for wellness checks during 
the interim period between EOT and EOS.
4.4.3
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 timepoint prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including non-prescription herbal treatments, vitamins, invasive and 
diagnostic procedures) received within 14 days prior to the screening visit (visit 1) and through 
the end of study (ie, including the protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 14 days of the first dose of investigational 
product, but discontinued before the first dose of investigational product. 
5.2
Concomitant Treatment
Concomitant medications are those that continue after the start of investigational product or are 
newly introduced after the start of treatment through the end of study. In all instances the start 
date of prior and concomitant therapies must be recorded to the extent possible.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
Changes in any medication and/or dosage will be recorded on the eCRF. See also nutritional 
support in Section 7.2.15.2.
5.3
Prohibited Treatment
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The following prior therapies are excluded within the timeframes noted (see Section 4.2).
Prior Therapy
Time Restriction Prior to 
Screening
Native/synthetic glucagon-like peptide-2
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy used to treat inflammatory bowel disease (eg, antitumor 
necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Teduglutide for subcutaneous (SC) injection is provided in 3 mL vials containing 5 mg or 
1.25 mg teduglutide as a lyophilized powder that must be reconstituted using 0.5 mL with sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the investigator’s brochure.
6.1.1
Blinding of the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product
A dose of 0.05 mg/kg/day of teduglutide will be administered once daily to the subjects for 
24 weeks. The dose calculation will be based on body weight measured at the baseline visit 
(visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with the Shire medical monitor or designee.
Before the first dose of teduglutide or implementation of any change in ancillary kit components, 
subjects and/or any designated person who will be administering the investigational product will 
be trained by the investigator or a qualified designee on investigational product preparation and 
administration. After being trained, the trainee must perform the entire procedure correctly using 
the provided training materials and without coaching, including demonstration of proper 
technique for injecting the placebo into an injection simulation device. Subjects should not be 
injected with the placebo.
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. If a dose is delayed, that 
day’s dose should be administered as soon as possible, but consecutive doses should be separated 
by at least 12 hours.
The first SC injection should be administered under the supervision of the investigator or 
designee and the subject observed for hypersensitivity reactions for at least 4 hours during their 
initial dosing visit. The site of administration (arm, thigh, abdomen) of the first teduglutide dose 
must be specified and recorded in the eCRF. Detailed instructions for reconstitution and injection 
of the investigational product can be found in the Instructions for Use. Each day, the injection 
site should be rotated. 
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6.2.1
Allocation of Subjects to Treatment 
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day as described in 
Section 6.2. Subject numbers are assigned to all subjects as consent/assent to take part in the 
study is provided. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. These 
numbers will be used to identify the subjects throughout the study period. Once a number/unique 
identifier has been assigned, that number must not be used again if, for example, a subject is 
withdrawn from the study. If a unique identifier is allocated incorrectly, the study monitor must 
be notified as soon as the error is discovered.
6.3
Labeling, Packaging, and Storage
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 Practices.
6.3.2
Storage
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 and 8oC
until dispensed to a subject. The pre-filled sterile water for injection syringes will be stored at a 
temperature between 2 and 25°C. Once dispensed/supplied to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25oC). Parent/legally-authorized representative will be instructed to keep the subject’s 
investigational product and sterile water diluent at controlled room temperature. If there are 
concerns that the controlled room temperature cannot be maintained, the investigational product
may be refrigerated.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the study visits at which the subject is required to be at 
the clinic. Each investigational product kit is sufficient for a treatment period of 1 week and 
enough kits will be supplied to cover the period until the next planned study visit. Additional 
study kits will be provided as necessary.
Each subject will be given the investigational product according to his/her treatment assignment. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. All dispensed medication will be documented on the eCRFs and/or other 
investigational product record. The investigator is responsible for assuring the retrieval of all 
study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects. 
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.
See the Pharmacy Manual for additional information.
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6.5
Treatment Compliance
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by reviewing the subject diaries and asking the subject or 
the subject’s parent or legally-authorized representative if they have administered the 
investigational product according to instructions. If any doses have been missed, the reason for 
missed dose should be documented in the subject’s source documentation including, as 
applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. Subjects falling outside of these parameters will not be included in the per-protocol 
efficacy analyses (see Section 9.6).
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7
STUDY PROCEDURES
7.1
Study Schedule
Subject evaluations will be performed during the indicated days and weeks of the study as 
provided in the Study Schedules (Table 1 and Table 2).
All data collected are to be recorded on the appropriate eCRF.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1.1
Screening
All subjects’ parents/legally-authorized representatives must sign an informed consent form and, 
if applicable, subjects must sign an informed assent form prior to initiation of any study-related 
procedure. All subjects will be screened for a minimum of 2 weeks. Attempts should be made to 
limit the screening period to 4 weeks.
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigation product. 
At the discretion of the investigator, subjects who fail screening may be re-screened one time 
with prior sponsor approval. In the event of re-screening, a new subject number will be assigned
to the subject and the subject will also be re-consented.
7.1.2
Treatment Period
Subjects who meet all eligibility criteria at screening, and eligibility criteria are confirmed at 
visit 2/baseline, will be enrolled in the study and will receive the first dose of investigational 
product at the baseline visit (visit 2). Subjects will enter a 24-week treatment period consisting of 
either visits or scheduled weekly telephone contacts as outlined in the Section 3.1.
7.1.3
Follow-up Period
During the 4-week follow-up period, weekly telephone visits will be conducted on week 25 to 
week 27 followed by the EOS visit (week 28). Similar to assessments performed during the 
treatment period, phone visits during follow-up will include review of intake diaries, and 
adjustment of nutritional support as needed (see Section 3.1). Procedures to be performed at the 
EOS visit (week 28) are specified in the Study Schedules (Table 1 and Table 2); subjects will be 
queried on serious adverse events (SAEs), AEs, and concomitant treatments, and all AEs and 
SAEs that are not resolved at the time of this visit will be followed to closure (see Section 8.1).
7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (and, when 
applicable, informed assent) must be obtained from the subject’s parent(s) or legally authorized 
representative(s) and from the subject (if applicable).
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The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legally authorized representative 
by the investigator or designee in accordance with the guidelines described in Section 10.3.1. 
Documentation and filing of informed consent documents should be completed according to 
Section 10.2.
7.2.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria by 
the investigator or designee. Subjects who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the subject’s ineligibility for the study will 
be documented.
7.2.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at 
baseline by the investigator or designee on the basis of review of the study entrance criteria.
7.2.4
Demographics and Other Baseline Characteristics
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy

GI-specific symptoms history (Section 7.2.15.1)

Physical examination, including body weight, height (or length), and head circumference (up 
to 36 months of age), and trends on growth charts

Vital signs including temperature, heart rate, and blood pressure

Prior medications (medications used within 14 days prior to screening and discontinued prior 
to the first dose of investigational product), including drug name, dose, route, reason for use, 
and therapy dates. Medications used during the treatment period (after the first dose of 
investigational product) will be recorded as concomitant medications.

Electrocardiogram (ECG) (12-lead) variables include general findings (normal/ abnormal, 
not clinically significant/ abnormal, clinically significant). The cause of any clinically 
significant ECG will be specified.

Laboratory test results: biochemistry, hematology, coagulation, and urinalysis

Plasma citrulline levels

Presence of antibodies to teduglutide and titer level, if present

Gastrointestinal imaging/testing (upper GI series with small bowel follow-through 
[UGI/SBFT], abdominal ultrasound, colonoscopy or sigmoidoscopy, fecal occult blood)
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
Pregnancy testing for females of childbearing potential

Nutritional support prescriptions (eg, PN/IV and enteral nutrition [EN] volume and calories, 
PN/IV hours per day and days per week) (Section 7.2.15.2)

Nutritional support diary data (Section 7.2.15.3)
7.2.5
Pharmacokinetic Assessments
Pharmacokinetic assessments are listed in Section 9.10.1. 
Blood samples for teduglutide concentrations will be collected at the baseline and week 4 visits. 
If blood samples are not/cannot be collected at week 4, the uncollected samples can be collected 
during any future site visit while the subject is still on investigational product. A schedule of PK 
sample collection is provided in Table 4. Instructions for sample collection and handling are 
included in the Laboratory Manual.
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing
Study week
Baseline
Week 4
Visit Number
2
6
Hour
0a
1
6
0a
2
4
a Prior to investigational product administration
The timepoints indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these timepoints may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

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 (at the week 4 draw).

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes

6-hour postdose draw: ±30 minutes
At PK timepoints, the date and time of investigational product administration and blood 
collection must be recorded on the eCRF.
7.2.6
Physical Examination (Including Height and Weight)
Physical examinations will be performed, and body weight, height (or length), and head 
circumference (up to 36 months of age) measured according to the Study Schedules (Table 1 and 
Table 2).
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Physical examinations will be performed by the investigator during the study 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.
Subjects should be weighed on the same scale at each study visit. Height (or length [cm]) and 
head circumference (for subjects ≤36 months of age[cm]) will be measured at selected visits.
Body mass index (BMI) and z-scores for weight, height (or length), head circumference, and 
BMI will be calculated by the sponsor. 
7.2.7
Vital Signs
Vital signs will be measured according to the Study Schedules (Table 1 and Table 2). 
Measurements will include body temperature (°C), heart rate (beats per minute), and systolic and 
diastolic blood pressure (mmHg). 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.
7.2.8
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing according to the Study Schedules (Table 1 and Table 2). Subjects should be in a seated or 
supine position during blood collection.
Laboratory collections required at intervals that do not coincide with site visits (safety laboratory
assessments eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at 
the investigational site. 
Clinical laboratory tests will include the following (see Table 5):
Table 5
List of Laboratory Tests
Hematology:
Hematocrit 
Hemoglobin 
Platelet count
Red blood cell (RBC) count 
RBC morphology, if needed
White blood cell count with differential
Coagulation:
Prothrombin time/International  normalized ratio 
will be measured in all subjects at screening and 
subsequently if confirmed drug-induced liver 
injury (DILI) is suspected (Section 8.4.2)
Biochemistry:
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
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Table 5
List of Laboratory Tests
Urinalysis: 
Blood
Glucose
Leucocytes
Microscopic analysis
pH 
Protein
Specific gravity
Pregnancy tests (females of childbearing potential):
Serum β-HCG (screening)
Urine β-HCG (all other visits)
C-reactive protein 
Creatinine
Estimated glomerular filtration rate 
(Schwartz formula)
Gamma-glutamyl transferase 
Glucose
Lipase
Magnesium
Phosphorus
Potassium 
Sodium 
Triglycerides
Uric acid
For children in diapers, urine specimen collection should be attempted as part of the safety lab
assessments, but lack of urinalysis will not constitute a protocol deviation.
7.2.9
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass. Blood samples will
be collected 2 to 4 hours postprandial, whenever possible, at the timepoints specified in the 
Study Schedules (Table 1 and Table 2). Samples may be drawn from a central line or peripheral 
access and processed according to instructions in the Laboratory Manual. 
7.2.10
Antibody Assessments
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the baseline visit (day 0) and at least 14 hours after the previous 
dose at the EOT visit (week 24 or early termination); samples may be drawn from a central line 
or peripheral access. One additional sample will be collected at the EOS 4 weeks after the EOT 
(ie, week 28 or EOS). 
If a blood sample tests positive for anti-teduglutide antibodies at week 28 or EOS, then the 
subject will be retested 3 months after EOT. If that sample tests positive, then the subject will be 
retested 6 months after EOT.
7.2.11
Pregnancy Testing
Any female subject of childbearing potential (Section 4.3) must have negative pregnancy tests to 
enroll or continue in the study. Pregnancy tests will be performed at screening (serum β-HCG 
testing) and at all site visits (urine β-HCG testing). 
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7.2.12
Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study.
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than one blood assessment 
is to be done at the same timepoint, the assessments should be combined if they require the same 
type of tube.
7.2.13
Electrocardiogram
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) 
as indicated in the Study Schedules (Table 1 and Table 2). Electrocardiogram recordings will be 
read locally by an experienced physician. Results (normal; abnormal, not clinically significant;
and abnormal, clinically significant with a description of the abnormality) will be recorded on 
the eCRF. 
7.2.14
Gastrointestinal-specific Testing
Gastrointestinal testing will be performed as needed for all subjects during the screening period, 
as indicated in sections 7.2.14.1 to 7.2.14.4. Follow-up testing will be performed as needed
according to the guidelines noted in sections 7.2.14.1 to 7.2.14.4 and the Study Schedules (Table 
1 and Table 2).
7.2.14.1
Upper Gastrointestinal Series with Contrast
An UGI/SBFT will be performed following the ingestion of barium contrast material during the 
screening period. Results from procedures performed within 6 months prior to visit 1 will also be 
acceptable.
7.2.14.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to visit 1 will also be acceptable.
7.2.14.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, week 12, and week 24 (EOT). 
Subjects with positive fecal occult blood testing results at screening or at week 24 for whom a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy. Subjects with positive fecal occult blood testing results at week 12 for which a 
cause is not identified by a physical examination will be discussed with the Shire medical 
monitor or designee. If clinically indicated, an esophagogastroduodenoscopy (EGD) may also be 
performed with any colonoscopy or sigmoidoscopy.
Subjects with negative endoscopy findings at screening may enroll in the study.
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Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with Shire’s medical monitor or designee, the subject is 
considered appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with Shire’s medical monitor or designee, the 
subject is considered inappropriate to be enrolled in the study.
7.2.14.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy or sigmoidoscopy at screening. 
If the fecal occult blood testing is negative at screening and the procedure was performed within 
1 year before the screening visit (visit 1), then those prior results are acceptable for the screening 
assessment.
Children younger than 12 years will undergo the procedure if they test positive for fecal occult 
blood at screening and the cause is not identified by physical examination (see Section 7.2.14.3).
Requirements for colonoscopy or sigmoidoscopy in response to positive fecal occult blood 
testing at weeks 12 or 24 are presented in Section 7.2.14.3.
7.2.15
Other Study Procedures
7.2.15.1
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/legally-
authorized representative in a GI-specific symptoms history diary on a daily basis. At the 
baseline visit, the investigator will review the GI-symptoms diary and summarize the findings.
7.2.15.2
Nutritional Support
Nutritional support includes PN/IV and EN. Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status,
and safety laboratory results. Guidelines for nutritional support management and weaning 
algorithms are provided in Appendix 2 and Appendix 3, respectively.
Intake diaries will be used to collect and evaluate each subject’s nutritional support.
7.2.15.3
Diaries
The subject/parent/legally-authorized representative will complete the appropriate fields of the 
PN/IV and EN (formula) sections of the intake diary.
Intake diary:  The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:
PN/IV volume and infusion duration
EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
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Output diary:  Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every site visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc. The subject or parent will 
perform dipstick specific gravity tests on the first urine produced after the daily 
infusions of PN/IV support.

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first 
void after the daily PN/IV infusion to measure specific gravity.

Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency 
using the Bristol Stool Form Scale (see output diary)

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine 
and stool) as stool output and score the stool consistency using the Bristol Stool 
Form Scale (see output diary). Stool volume will be calculated using the formula:
1 g (scale weight) = 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
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8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 3.2. This includes events occurring during the screening phase 
of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Note that the severity of AEs listed in Table 6 that may lead to dose interruption based on known 
risks of teduglutide will also be evaluated using the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria (Section 8.4.1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
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, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the 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 end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment 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, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 3.2.
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 SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) 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 the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol as well as the Shire 
Investigational and Marketed Products Pregnancy Report Form. The test date of the first positive 
serum/urine β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Administration of a dose greater than the allocated dose of investigational 
product or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event. 
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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. 
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 
e-mail address can be found on the form (sent under separate cover). 
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed 
consent/assent is signed until the defined follow-up period stated in Section 3.2 and must be 
reported to Quintiles Transnational Japan K.K within 24 hours of the first awareness of the 
event.
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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 Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent form, or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
Quintiles Transnational Japan K.K is responsible for notifying the relevant regulatory 
authorities/central institutional review boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs. In addition the sponsor and/or designee is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the
teduglutide program. 
The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
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The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
For AEs of special interest, Quintiles Transnational Japan K.K Quintiles Transnational Japan 
K.K must be informed within 24 hours of first awareness as per the SAE notification instructions 
described in Section 8.2.2 even if the event does not fulfill seriousness criterion.
8.4
Dose Interruption of Individual Subjects 
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
Investigational product must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related to 
the investigational product. This does not include the presence of anti-teduglutide antibodies, 
mild injection site reactions or mild symptoms that according to the investigator do not pose 
a significant risk to the subject.

An AE listed in Table 6 that is of NCI CTCAE severity Grade 3 or 4 and considered to be 
related to the investigational product administration (see Section 8.4.1)

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The investigational product may be discontinued if the subject experiences an AE listed in Table 
6 that is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with 
Shire’s medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the DMC should be guided by the descriptions of Grade 3 and 4 events, as they 
relate to identified risks associated with the administration of teduglutide (see Table 6).
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent
intervention indicated
Intestinal obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening  consequences; urgent
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or
hospitalization indicated; nonemergent
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (total bilirubin >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification laboratory assessments and an 
inquiry should be made as to the presence of clinical symptoms consistent with new liver injury. 
The subject should be followed closely to determine the trajectory of the laboratory 
abnormalities and to evaluate the cause of liver injury. This evaluation may include, as clinically 
indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A immunoglobulin M [IgM], 
hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, Epstein-Barr virus
antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (anti-nuclear, 
anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), intestinal failure 
associated liver disease, cardiovascular causes such as ischemic hepatitis, and concomitant 
hepatotoxic treatments.
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Additional evaluations may be performed at the discretion of the investigator in consultation 
with Shire medical monitor or designee.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
investigational product.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

At least 2 subjects develop the same event listed in Table 6 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 6 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying disease 
process.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator or investigators’ authorized site personnel must enter the information required 
by the protocol in the eCRF. A study monitor will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the eCRF will be addressed by 
the investigator or qualified site personnel. When a data discrepancy warrants correction, the 
correction will be made by the investigator or authorized site personnel. The investigator must 
verify that all data entries in the eCRF are accurate and correct. Original diary data should be
entered into the eCRF and take precedence over data collected over the phone. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. Once a subject is enrolled, it is expected that the investigator or authorized site 
personnel will complete the eCRF entry in a timely manner following the subject’s visit.
9.2
Clinical Data Management
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US Food and Drug Administration (FDA) 21 CFR Part 11 Guidance. The 
clinical trial database will include an audit trail to document any evidence of data processing or 
activity on each data field by each user. 
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Pharmacovigilance and Risk Management database.
9.3
Statistical Analysis Process
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.
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Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
All statistical analyses will be performed using SAS®.
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design.
9.4.1
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by Shire, independent contractors hired by Shire, or members of regulatory 
agencies. The DMC may make recommendations to Shire regarding stopping, modifying or 
continuing the study; however, Shire will have the final responsibility to determine whether the 
study should be modified or temporarily or permanently stopped. 
Safety and tolerability results will be evaluated by a DMC which will convene approximately 
every 3 months during the active study period (date of the first subject’s first dose to date of the 
last subject’s last dose), based on subject enrollment. The DMC review will include all 
cumulative safety data from study assessment through the end of each review period.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation.
9.6
Study Population
Subjects are considered enrolled in the study when they meet all eligibility criteria at screening 
and eligibility criteria are confirmed at visit 2/baseline.
The ITT population is defined as any subjects who were enrolled into the study. The safety 
population is defined as the subset of ITT with subjects who received at least 1 administration of 
investigational product with any safety follow-up. The primary population analyzed for 
efficacy/PD will be the ITT population. 
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An additional per-protocol population analysis will also be performed as secondary/sensitivity 
analysis. The per-protocol population is defined as the subset of subjects in the ITT population 
without a major protocol deviation. Details will be prospectively defined in the final SAP prior to 
database lock.
The PK analysis population is defined as all subjects in the safety analysis population for whom 
the primary PK data are considered sufficient and interpretable.
9.7
Demographics and Baseline Characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories) will be presented, as appropriate, to 
summarize the demographic and baseline variables.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized. 
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with specific histories 
will be summarized by system organ class and preferred term.
9.8
Efficacy/Pharmacodynamic Analyses
The efficacy/PD endpoints include:

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) 
compared to baseline

≥20% reduction in PN/IV volume at each visit

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, to 
week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
No formal statistical test will be performed due the limited sample size.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
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9.9
Safety Analyses
The safety and tolerability variables include:

Adverse events, including those pertaining to GI symptoms

Body weight, height (or length), head circumference (up to 36 months of age), and trends on 
growth charts

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis) including the 
following lab tests at all site visits and interim safety labs to detect hepatotoxicity signals:  
AST, ALT, ALP, and bilirubin

Urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal 
occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment-emergent AEs will be summarized by 
system organ class and preferred term. The number and percentage of subjects with AEs, SAEs,
AEs that lead to discontinuation, investigational product-related AEs (determined by the 
investigator), and AEs that resulted in a fatal outcome will be summarized. AEs will also be 
summarized with regard to intensity and relationship to investigational product. For AEs of 
special interest, the CTCAE grading system will be used as described in Section 8.4.1.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies.
9.10
Other Analyses
9.10.1
Pharmacokinetic Analyses
The following PK parameters will be estimated based on measured teduglutide plasma 
concentrations using a population PK modeling approach:

Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)
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
AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Cmax at steady state (Cmax,ss)

Minimum plasma concentration at steady state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics for PK parameters (mean, median, standard deviation, minimum and 
maximum values, geometric mean) will be calculated.
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10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee ensures that local regulatory authority requirements are met before the 
start of the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior to 
release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor or designee is responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries may include participating 
investigators’ names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
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10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor or designee before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent/assent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will 
promptly inform the sponsor and the IRB/EC and provide them with a detailed written 
explanation. The investigator will also return all investigational product, containers, and other 
study materials to the sponsor. Upon study completion, the investigator will provide the 
sponsor, IRB/EC, and regulatory agency with final reports and summaries as required by 
international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is 
provided at all phases during the study, may be done by the sponsor, applicable contract 
research organization, investigator, or for multicenter studies, the coordinating principal 
investigator according to national provisions and will be documented in the investigator 
agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms will be supplied by the sponsor or designee and should be handled 
in accordance with instructions from the sponsor.
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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 solely onto the eCRF.
All data transmitted to the sponsor or designee must be endorsed by the investigator. The study 
monitor will verify the contents against the source data per the monitoring plan. If the data are 
unclear or contradictory, queries will be sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to subject’s 
medical file, subject diaries, and original clinical laboratory reports, and imaging reports. All key 
data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the 
Pharmaceuticals and Medical Devices Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator receives from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator or designee to obtain written informed consent from 
all subjects or parents/legally-authorized representatives, and assent from subjects where 
applicable, prior to any study-related procedures including screening assessments. 
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All consent and assent documentation must be in accordance with applicable regulations and 
GCP. Each subject or the subject’s parent or legally-authorized representative, as applicable, is 
requested to sign and date the informed consent form/assent, or a certified translation if 
applicable, after the subject has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent/assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent or legally-authorized representative, as applicable. This document requires
translation into the local language. Signed consent/assent forms must remain in each subject’s 
study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form and assent 
form where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent
document (approved by the sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. Responsibility for coordinating with IRBs/ECs is defined in the 
investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor or designee has received 
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies 
this can be done by the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
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10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) 
which gave approval for the study to proceed. The sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11 LIST OF REFERENCES
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Kitajima, M., Shamizu, M., Wakabayashi, G., Hoshino, K., Tanabe, M. & Kawachi, S. 2013. 
Current Issues in Liver and Small Bowel Transplantation, Springer Science & Business 
Media.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D., Boctor, D., Brindle, M., Lam, V. & Robertson, M. 2011. Elements of successful 
intestinal rehabilitation. J Pediatr Surg, 46, 150-6.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Takagi, Y., Okada, A., Sato, T., Fukushima, T., Shirotani, N., Osawa, Y., Takeyama, H., 
Taniguchi, M., Takehara, H. & Mizote, H. 1995. Report on the first annual survey of 
home parenteral nutrition in Japan. Surg Today, 25, 193-201.
Takehara, H. 2001. Home parenteral nutrition for pediatric patients. Nihon Rinsho, 59 Suppl 5, 
848-51.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
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12 APPENDICES
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
18 Dec 2015
Global
Amendment 1
27 Apr 2016
Global
Amendment 2
06 Jun 2017
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Age range for subjects has been specified. Subjects will be 1 year through 
15 years of age. 
Title page
Protocol signature page
Synopsis
Sections 4 and 4.1
Emergency contact information has been updated.
Emergency Contact Information
Sections 8.1.6, 8.2.2, 8.2.4
Clarification that departing from the nutritional support adjustment 
guidelines and weaning algorithms in Appendix 2 and Appendix 3, 
respectively, will not constitute a protocol deviation. 
Synopsis
Section 3.1
Statement added that subjects who complete the study may participate in a 
long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Section 3.1
Inclusion and Exclusion criteria have been refined and clarified; there were 
no criteria added with the exception of the age of subject population which 
has been added as an inclusion criterion (was previously in introductory 
sentence).
Synopsis
Sections 4.1 and 4.2
Exclusion Criterion #11 has been updated to indicate that a subject would 
be excluded from the study if the subject had participated in a clinical study 
of experimental drug within 3 months or 5.5 half-lives of the experimental 
drug, whichever is longer.
Synopsis
Section 4.2
Efficacy/PD endpoints have been lumped together and clarified. The small 
population does not warrant primary versus secondary endpoints. The 
statistical method has been clarified.
Synopsis
Section 9.8
Safety assessments and statistical methods have been clarified. 
Synopsis
Section 9.9
Study schedule of events tables have been revised to reflect the changes to 
the protocol and for clarity.
Table 1
Table 2
Any phone contacts may be replaced with unscheduled site visits if 
necessary.
Table 1
Table 2
Section 3.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Requirement added that female subjects of child-bearing potential undergo 
a serum-based pregnancy test at screening.
Table 1
Table 2
Sections 4.3, 7.2.8, 7.2.11
Definition of prior and concomitant medications has been expanded to 
include invasive and diagnostic procedures.
Table 1
Table 2
Section 5
Additional information on selection of teduglutide dosing regimen and 
duration in the study has been inserted.
Section 2.1
Frequency of Data Monitoring Committee meetings has been specified.
Sections 3.1 and 9.4.1
Definition of screening period has been clarified.
Section 3.2
Inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy for symptom control has been removed from 
the list of excluded disease and illness in Exclusion Criterion #24.
Section 4.2 (Table 3)
Definition of acceptable methods of contraception has been revised to 
reflect available methods in Japan.
Section 4.3
List of prohibited prior therapy has been revised to remove experimental 
antibody treatment, as it is now included in the revised exclusion 
criterion #11.
Section 5.3
Requirement that teduglutide should be administered in the morning has 
been removed.
Section 6.2
Language on labeling, packaging, and drug accountability has been 
clarified.
Sections 6.3 and 6.4
Reviewing subject diaries has been included in the subject compliance with 
dosing check. Clarification that attempts should be made by the investigator 
to contact the sponsor or designee prior to dose interruption has been 
added.
Section 6.5
Requirement has been added that subjects who are re-screened must be re-
consented.
Section 7.1.1
Timeframe for a subject to be considered enrolled in the study has been 
clarified.
Sections 7.1.2 and 9.6
Demographics and other baseline characteristics have been clarified.
Section 7.2.4
Windows for PK blood collection have been extended; possibility to collect 
week 4 timepoint at any future visit if needed has been added.
Section 7.2.5
PT/INR testing has been added at screening and subsequently if confirmed 
drug-induced liver injury (DILI) is suspected thereafter.
Table 1
Table 2
Section 7.2.8
For children in diapers, urine specimen collection should be attempted as 
part of the safety lab assessments, but lack of urinalysis will not constitute a 
protocol deviation.
Table 1
Table 2
Section 7.2.8
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Timeframe of follow-up for subjects with blood samples testing positive for 
anti-teduglutide antibodies at week 28 or EOS has been clarified.
Synopsis
Table 1
Table 2
Section 7.2.10
Need for a subject with a positive fecal occult blood testing at week 12 
without a readily identifiable cause by physical examination to undergo a 
colonoscopy or sigmoidoscopy is now open to discussion with the Shire 
medical monitor or designee.
Table 1
Table 2
Section 7.2.14.3
Need for children younger than 12 years to undergo a colonoscopy or 
sigmoidoscopy if they test positive for fecal occult blood at screening and 
the cause is not identified by physical examination has been specified.
Section 7.2.14.4
GI symptoms history worksheet has been renamed GI-specific symptoms 
history diary, and details on recording and reviewing symptoms have been 
added. 
Table 1
Table 2
Section 7.2.15.1
“Other nutrition (regular diet and drink)” has been removed from the Intake 
diary.
Section 7.2.15.2
Output diary data collection will continue to occur over a 48-hour period of 
PN/IV and EN stability before every site visit. Between site visits, the 
output diary collection will only be required within 1 week of 
implementing a change in the PN/IV prescription.
Table 1
Table 2
Section 7.2.15.3
Severity categorization has been updated to specify that the severity of AEs 
listed in Table 6 that may lead to dose interruption based on known risks of 
teduglutide will also be evaluated using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grading criteria.
Section 8.1.1
Definition of an overdose to teduglutide has been revised.
Section 8.1.7
Adverse events of special interest have been redefined and procedures for 
reporting them have been added.
Section 8.3
More information has been provided on criteria for dose interruption of 
individual subjects. Dose discontinuation has been made absolute for an AE 
known to be a risk associated with teduglutide administration (Table 6) that 
is of NCI CTCAE severity ≥Grade 3 and considered to be related to 
investigational product; cases of severe hypersensitivity that are determined 
to be related to investigational product; DILI that is related to 
investigational product; and pregnancy. SAEs related to investigational 
product are potential but not absolute reasons for dose discontinuation.
Sections 8.4, 8.4.1, and 8.4.2
Criteria for DILI have been added.
Section 8.4.2
Criteria for early termination of the study have been clarified.
Section 8.5
Clarification that original diary data should be entered into the eCRF and 
take precedence over data collected over the phone.
Section 9.1
Definition of PK analysis population has been added.
Section 9.6
Pharmacokinetic analyses methods and parameters have been clarified.
Synopsis
Section 9.10.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Protocol history has been added in Appendix 1.
Appendix 1
Guidelines for nutritional support management during the study have been 
clarified.
Appendix 2
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APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY (SHP633-302)
Nutritional support adjustment in volume and calories should be considered at all planned visits.
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should be considered for managing nutritional support 
(PN/IV and EN [PN/EN]) in terms of volume and calories during the treatment period:

Growth trajectory, including weight, height (or length), and head circumference (for children 
up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen/creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Form Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food and fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.
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APPENDIX 3
WEANING ALGORITHMS  
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in Diapers
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Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers
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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment
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CLINICAL TRIAL PROTOCOL: SHP633-302
TITLE:
A 24-week Safety, Efficacy, Pharmacodynamic, and 
Pharmacokinetic Study of Teduglutide in Japanese Pediatric 
Subjects, Aged 1 Year through 15 Years, with Short Bowel 
Syndrome who are Dependent on Parenteral Support
NUMBER:
SHP633-302
PHASE:
3
DRUG:
Teduglutide 
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421 USA
 
PROTOCOL 
HISTORY:
Amendment 3: 24 Jan 2018
Amendment 2: 06 Jun 2017
Amendment 1: 27 Apr 2016
Original Protocol: 18 Dec 2015
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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SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
I 
, MD PhD 
 
Global Clinical 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-302. 
Title: A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 1 Year through 15 Years, 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 or subject's guardian in order to obtain their 
consent/assent 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 Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and 
Address: 
(please hand print or type) 
Signature: 
Date: 
Shire
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PROTOCOL SIGNATURE PAGE
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
Amendment Date
24 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated the emergency contact information for the study.
Emergency Contact Information
Updated the product quality complaint section to address the drug 
delivery device.
Product Quality Complaints
Revised study drug administration language for clarity.
Section 6.1.2
As requested by PMDA, updated text to specify the process for training 
parent/guardian and measures to be taken to provide oversight on study 
drug administration.
Synopsis, Table 1, Section 6.1.2.1
Clarified that the study drug administration diary can be completed by 
study site staff.
Table 1, Section 6.4, 
Section 7.2.15.3
Added direct bilirubin to the list of laboratory tests.
Table 5
Replaced the term “legally authorized representative” with guardian.
Throughout protocol
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol
See Appendix 1 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event, the investigator must fax or e-mail the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to Quintiles Transnational Japan K.K using the details 
below. 
In-country Clinical Caretaker:
 
, 
: 
Quintiles Transnational Japan K.K
Phone: 
Email:
Fax: 
Pharmacovigilance SAE Reporting:
FAX: 
 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 between 8:00 to 20:00 US Eastern Standard 
Time, the investigator may contact the Shire medical monitor:
, PharmD, MSc
Lead Clinical Development Scientist
Office Phone: 
Mobile Phone: 
Email:
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting adverse events 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
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF IN-TEXT TABLES ........................................................................................................10
LIST OF IN-TEXT FIGURES.......................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES..................................................................................................................17
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background and Clinical Information ........................................................22
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Clinical Study...............................................................................25
2.2
Objective(s) ..............................................................................................................25
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................31
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Subject Withdrawal Criteria ..................................................................................31
4.4.2
Reasons for Discontinuation..................................................................................31
4.4.3
Subjects “Lost to follow-up” Prior to Last Scheduled Visit..................................32
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.1
Prior Treatment ........................................................................................................33
5.2
Concomitant Treatment............................................................................................33
5.3
Prohibited Treatment................................................................................................33
6
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Blinding of the Treatment Assignment..................................................................34
6.1.2
Administration of Investigational Product.............................................................34
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6.1.2.1
Administration by Parent/Guardian .......................................................35
6.1.3
Allocation of Subjects to Treatment ......................................................................36
6.2
Labeling, Packaging, and Storage............................................................................36
6.2.1
Labeling and Packaging.........................................................................................36
6.2.2
Storage ...................................................................................................................36
6.3
Drug Accountability.................................................................................................36
6.4
Treatment Compliance .............................................................................................38
7
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening................................................................................................................39
7.1.2
Treatment Period....................................................................................................39
7.1.3
Follow-up Period ...................................................................................................39
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Informed Consent...................................................................................................40
7.2.2
Study Entrance Criteria..........................................................................................40
7.2.3
Confirmation of Study Eligibility..........................................................................40
7.2.4
Demographics and Other Baseline Characteristics................................................40
7.2.5
Pharmacokinetic Assessments ...............................................................................41
7.2.6
Physical Examination (Including Height and Weight)..........................................42
7.2.7
Vital Signs..............................................................................................................42
7.2.8
Clinical Laboratory Tests.......................................................................................42
7.2.9
Plasma Citrulline....................................................................................................43
7.2.10 Antibody Assessments...........................................................................................43
7.2.11 Pregnancy Testing..................................................................................................44
7.2.12 Volume of Blood....................................................................................................44
7.2.13 Electrocardiogram..................................................................................................44
7.2.14 Gastrointestinal-specific Testing ...........................................................................44
7.2.14.1
Upper Gastrointestinal Series with Contrast ..........................................44
7.2.14.2
Abdominal Ultrasound ...........................................................................44
7.2.14.3
Fecal Occult Blood Testing....................................................................44
7.2.14.4
Colonoscopy/Sigmoidoscopy.................................................................45
7.2.15 Other Study Procedures .........................................................................................45
7.2.15.1
GI-specific Symptoms History...............................................................45
7.2.15.2
Nutritional Support.................................................................................45
7.2.15.3
Diaries ....................................................................................................46
8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ....................................47
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................47
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8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................48
8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Symptoms of the Disease Under Study .................................................................49
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................49
8.1.6
Pregnancy...............................................................................................................49
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................50
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................51
8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................52
8.2.6
Fatal Outcome........................................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................52
8.3
Adverse Events of Special Interest...........................................................................52
8.4
Dose Interruption of Individual Subjects .................................................................53
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide.......................53
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury...........................55
8.5
Early Termination of the Clinical Study ..................................................................57
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................58
9.1
Data Collection.........................................................................................................58
9.2
Clinical Data Management.......................................................................................58
9.3
Statistical Analysis Process......................................................................................58
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......59
9.4.1
Data Monitoring Committee..................................................................................59
9.5
Sample Size Calculation and Power Considerations................................................59
9.6
Study Population ......................................................................................................59
9.7
Demographics and Baseline Characteristics ............................................................60
9.8
Efficacy/Pharmacodynamic Analyses......................................................................60
9.9
Safety Analyses........................................................................................................61
9.10
Other Analyses .........................................................................................................61
9.10.1 Pharmacokinetic Analyses.....................................................................................61
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................63
10.1
Sponsor’s Responsibilities .......................................................................................63
10.1.1 Good Clinical Practice Compliance.......................................................................63
10.1.2 Public Posting of Study Information......................................................................63
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10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................63
10.1.4 Study Suspension, Termination, and Completion..................................................63
10.2
Investigator’s Responsibilities .................................................................................64
10.2.1 Good Clinical Practice Compliance.......................................................................64
10.2.2 Protocol Adherence and Investigator Agreement..................................................64
10.2.3 Documentation and Retention of Records.............................................................64
10.2.3.1
Case Report Forms.................................................................................64
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................65
10.2.3.3
Financial Disclosure...............................................................................65
10.3
Ethical Considerations..............................................................................................65
10.3.1 Informed Consent...................................................................................................65
10.3.2 Institutional Review Board or Ethics Committee..................................................66
10.4
Privacy and Confidentiality......................................................................................67
10.5
Study Results/Publication Policy .............................................................................67
11 LIST OF REFERENCES........................................................................................................69
12 APPENDICES ........................................................................................................................70
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LIST OF IN-TEXT TABLES
Table 1
Study Schedule of Events – Screening to Week 12...................................17
Table 2 
Study Schedule of Events  – Weeks 13 to 28 ............................................20
Table 3
Examples of Excluded Diseases and Illnesses...........................................30
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing.............41
Table 5
List of Laboratory Tests.............................................................................42
Table 6
Adverse Events that May Lead to Dose Interruption.................................54
LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram ..........................................................................................27
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-inf
AUC of zero to infinity
AUC0-t
AUC from zero to the last measurable concentration
AUCss
AUC at steady state
BMI
body mass index
Cmax
maximum plasma concentration
Cmax,ss
Cmax at steady state
Cmin, ss
minimum plasma concentration at steady state
CL/F
apparent clearance
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EC
ethics committee
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
US Food and Drug Administration
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GCP
Good Clinical Practice
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
IgM
immunoglobulin M
INR
international  normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
NCI
National Cancer Institute
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
PN/EN
parenteral nutrition/ intravenous fluids and enteral nutrition
PN/IV
parenteral nutrition/intravenous fluids
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow-through
ULN
upper limit of normal
US
United States
Vλz/F
apparent volume of distribution
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STUDY SYNOPSIS
Protocol number: SHP633-302
Drug: Teduglutide
Study Title:
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of Teduglutide in Japanese 
Pediatric Subjects, Aged 1 Year through 15 Years, with Short Bowel Syndrome who are Dependent on 
Parenteral Support
Number of subjects: 
Planned enrollment is approximately 5 subjects.
Sites and Regions: Approximately 5 investigational sites in Japan are planned.
Study Duration:
There will be, at a minimum, a 2-week screening period followed by 24 weeks of   treatment. The end of 
study (EOS) visit will be scheduled at week 28, 4 weeks after the end of treatment (EOT) visit (week 24).
Investigational Product, Dose, and Mode of Administration: 
During the treatment period, a dose of 0.05 mg/kg/day of teduglutide will be administered once daily
subcutaneously (SC) to the subjects. 
The dose calculation will be based on body weight measured at the baseline visit (visit 2) and may be 
adjusted at week 12 (visit 14). No other adjustments to dose will be made during the study period, unless 
discussed with Shire medical monitor or designee.
The first dose of teduglutide will be administered by a study physician. The processes for training the 
parent/guardian to administer teduglutide and for providing oversight of study drug administration are 
described in the Site Training Guide.
Objective(s): 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and pharmacodynamics 
(PD), and pharmacokinetics (PK) of teduglutide in pediatric subjects (1 year through 15 years of age) with 
short bowel syndrome (SBS) who are dependent on parenteral support. 
Study Design:
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of teduglutide. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the requirements 
for nutritional support for each subject and to ensure adherence to eligibility parameters. Attempts should be 
made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the first 2 weeks 
(weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, and 12). For the remainder 
of the treatment period, visits at the sites will be conducted every 3 weeks (at weeks 15, 18, 21, and 24). 
Scheduled telephone contacts will be made on all other weeks during the treatment period. At all site visits 
and during telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. The EOS visit will be scheduled at week 28, 4 weeks following EOT. Weekly telephone 
contact will be made during the interim weeks from EOT to EOS to monitor safety and any changes in 
nutritional support. 
To maintain consistency across all centers, all attempts should be made to follow the nutritional support 
adjustment guidelines and weaning algorithms (developed with SBS expert input and to be provided in the 
protocol) for decisions regarding parenteral nutrition/intravenous fluids (PN/IV) support reduction and 
advances in enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability. 
Any departure from the nutritional support adjustment guidelines and weaning algorithms will not constitute 
a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have positive/specific 
antibodies, they will be asked to return for a follow-up visit 3 months post EOT for another antibody 
sample. If the subjects continue to have positive/specific antibodies at 3 months post EOT, they will be 
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asked to return for follow-up visit(s) up to 6 months post-treatment in order to determine their antibody 
status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee periodically during the 
active study period, based on subject enrollment.
All subjects who complete the study may participate in a long term extension study in which eligible 
subjects could receive teduglutide. 
Study Inclusion and Exclusion Criteria:
Subjects who satisfy the following inclusion and exclusion criteria will be enrolled in the study. 
Inclusion Criteria 
1.
Informed consent by a parent or guardian prior to any study-related procedures
2.
When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the 
subject prior to any study-related procedures 
3.
Male or female child or adolescent aged 1 year through 15 years
4.
Current history of SBS as a result of major intestinal resection (eg, due to necrotizing enterocolitis, 
midgut volvulus, intestinal atresia, or gastroschisis)
5.
Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or 
fluid/electrolyte needs
6.
Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually associated 
with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at 
least 3 months prior to and during screening, as assessed by the investigator. Transient instability for 
events such as interruption of central access or treatment of sepsis is allowed if the PN/IV support 
returns to within 10% of baseline prior to the event.
7.
Sexually active female subjects of childbearing potential must use medically acceptable methods of 
birth control during and for 4 weeks following the last dose of investigational product
Exclusion Criteria
1.
Subjects who are not expected to be able to advance oral or tube feeding regimens 
2.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of 
screening 
3.
Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and 
inability to reduce parenteral support 
4.
Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5.
Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
6.
Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done within 6 months 
prior to screening
7.
Major GI surgical intervention including significant intestinal resection within 3 months prior to 
screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections ≤ 10 cm, or 
endoscopic procedure is allowed)
8.
Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation 
9.
History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous 
basal or squamous cell carcinoma, or in situ non-aggressive and surgically resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 
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3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to screening and for the 
duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to 
screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to 
screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, antitumor 
necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant 
therapy that had been introduced or changed during the 3 months prior to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-related catheter 
sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the 
screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements within 1 
month prior to or during screening, excluding uncomplicated treatment of bacteremia, central line 
replacement/repair, or issues of similar magnitude in an otherwise stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the screening 
period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d.
Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results 
of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s)/guardian(s) and/or subjects who are not capable of understanding or not willing to adhere to 
the study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results. Examples 
of potential disease states/illnesses that may be excluded are listed in Table 3.
Pharmacokinetic Variables:
Blood samples for drug concentrations will be collected at the baseline visit (predose, at 1 and 6 hours 
postdose) and at week 4 visit (predose, 2 and 4 hours postdose). If blood samples are not/cannot be collected 
at week 4, the uncollected samples can be collected during any future site visit while the subject is still on 
investigational product. 
The following PK parameters will be derived using a population PK modeling approach:

Area under the plasma concentration–time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)

Area under the concentration-time curve at steady-state (AUCss)

Maximum plasma concentration (Cmax)

Maximum plasma concentration at steady-state (Cmax,ss)

Minimum plasma concentration at steady-state (Cmin,ss)

Time to Cmax (tmax)
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
Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Efficacy/Pharmacodynamic Assessments:
The efficacy/PD endpoints include: 

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), citrulline, 
and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) compared 
to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
Safety Assessments:
Safety and tolerability will be assessed by evaluating the following: 

Adverse events, including those pertaining to GI symptoms. 

Physical examinations, including body weight, height (or length), head circumference (up to 36 months 
of age), and trends on growth charts 

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms (ECGs)

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)  

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal occult blood 
testing, upper GI series with small bowel follow-through
Safety and tolerability will be evaluated by a Data Monitoring Committee during the study period.
Statistical Methods:
Due to the limited size of the study population, descriptive statistics will be used with a goal of summarizing 
the sample. As such, no claims of significance will be made for any of the data. 
Pharmacokinetic parameters will be estimated based on measured teduglutide plasma concentrations using a 
population PK modeling approach.
Continuous variables will be summarized using descriptive statistics including number of subjects, mean, 
median, standard deviation, maximum, and minimum. For categorical variables, statistical summaries will 
include number of subjects and percentages.
Efficacy/PD data will include change in PN/IV support, enteral nutritional support, plasma citrulline, and 
hours per day and days per week of PN/IV support, and will be summarized by visit.
Safety data will include clinical laboratory tests results; measurement of body weight, height (or length), and 
head circumferences (if applicable); vital signs; concomitant medications; and ECG monitoring; and will be 
summarized by visit. Adverse events will also be collected and summarized. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from baseline, if applicable. Frequency 
counts will be compiled for classification of qualitative safety data.
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STUDY SCHEDULES
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Informed 
consent/assenta
X
Eligibility
X
X
Demographics 
X
Medical /surgical 
history
X
Electrocardiogram
X
X
SBS history
X
Upper GI with small 
bowel follow-through 
and abdominal 
ultrasoundb
X
Fecal occult blood 
testingc
X
X
Colonoscopy/ 
sigmoidoscopyc
(X)
(X)
Provide GI-specific 
symptoms history diary
X
Review GI-specific 
symptoms history diary
X
Dispense 
investigational 
productd
X
X
X
X
X
X
X
X
Confirm administration 
proficiency
Xn
Xn
Xn
X
X
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Pharmacokinetic 
sampling
Xe
Xf
Safety laboratory testsg
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testingh
X
X
X
X
X
X
X
X
X
Plasma citrullinei
X
X
Antibodies to 
teduglutidej
X
Provide intake and 
output diaries
X
X
X
X
X
X
X
X
X
Review diaries and 
nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Physical examination/ 
vital signs/weight
X
X
X
X
X
X
X
X
X
Height (or length) and 
head circumferencem
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit.
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PK=pharmacokinetic; PT/INR=prothrombin time/international normalized ratio; 
PN/IV=parenteral nutrition/intravenous fluids; SBS=short bowel syndrome; SC=subcutaneous; UGI/SBFT= upper GI series with small bowel follow through
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
a
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b
If the subject has undergone an UGI/SBFT and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable for the 
screening assessments. If the subject has not had these procedures within the 6 months before visit 1 (screening), then the procedure(s) will be performed any time after 
providing informed consent with the results available and reviewed before the baseline visit (day 0).
c
All subjects enrolled will have a fecal occult blood test after providing consent/assent. Subjects with positive fecal occult blood test at screening for whom a readily 
detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or sigmoidoscopy. Colonoscopy or sigmoidoscopy will be conducted at screening on all 
subjects 12 years of age and older; however if the screening fecal occult blood test is negative and the subject has undergone the procedure within 1 year before visit 1 
(screening), then that result will be acceptable for the screening assessment (Section 7.2.14.4). Subjects with positive fecal occult blood test results at week 12 for which a 
cause is not identified by a physical exam will be discussed with the Shire medical monitor or designee (Section 7.2.14.3).
d
The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at 
least 4 hours. The site of administration (arm, thigh, abdomen) must be specified and recorded in the eCRF. The dose of study medication may be adjusted at week 12.
e
Baseline (visit 2) samples for PK analysis will be drawn predose, and 1 and 6 hours postdose (Section 7.2.5).
f
Week 4 (visit 6) samples for PK analysis will be drawn predose, and 2 and 4 hours postdose (Section 7.2.5).
g
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits (eg, 
biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine testing thereafter.  
i
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
j
Blood sample for antibody testing is to be collected at study site prior to first investigational product administration. Blood samples may be drawn from a central line or 
peripheral access (Section 7.2.10).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study by the subject or 
parent/guardian/study site staff (Section 7.2.15.3). Urine and stool output should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before 
every site visit and within 1 week of each change in PN/IV prescription. (Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section
7.2.15.2).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
m
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
n
The first dose of teduglutide will be administered by a study physician. The study physician must observe the parent/guardian administer the study drug in compliance with 
the study drug administration checklist at least twice before the parent/guardian is allowed to administer the drug without direct observation by the physician. Refer to 
Section 6.1.2.1.
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Table 2
Study Schedule of Events  – Weeks 13 to 28
Procedures
Week 
13
Week 14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(or 
EOT/ET)a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day 
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Dispense 
investigational product
X
X
X
Provide intake and 
output diaries
X
X
X
X
Review diaries and 
nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testsd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Pregnancy testinge
X
X
X
X
X
Plasma citrullinef
X
X
Antibodies to 
teduglutideg
X
X
Physical examination/
vital signs/weight
X
X
X
X
X
Height (or length) and 
head circumferenceh
X
X
X
X
X
Fecal occult blood 
testingi
X
Colonoscopy/ 
sigmoidoscopyi
(X)
Electrocardiogram
X
X
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Table 2
Study Schedule of Events  – Weeks 13 to 28
Procedures
Week 
13
Week 14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(or 
EOT/ET)a
Weeks 
25, 26, 27
Week 28 
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day 
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication/
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PN/IV=parenteral nutrition/intravenous fluid
a
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
d
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits 
(eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. Safety labs must be performed approximately 5-7 days following any 
adjustment to the PN/IV prescription. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy (urine testing). 
f
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9).
g
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, at least 14 hours after the previous dose of teduglutide. If a blood sample is positive for 
antibodies at week 28 or EOS, then the subject will be retested 3 months after EOT. If that sample is positive, then the subject will be retested 6 months after EOT. 
h
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
i
Subjects with positive fecal occult blood test at week 24 (EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory 
colonoscopy or sigmoidoscopy (Section 7.2.14.3).
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease that results in major surgical resections of the small intestine. In children, most 
cases of short bowel syndrome begin in infancy. Common causes of SBS in children include 
necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. (Duro et al. 2008; 
Squires et al. 2012) Similar to adults, new-onset SBS in older children usually stems from 
Crohn’s disease, trauma, and cancer. The diminished absorptive capacity for fluids and nutrients 
often results in dependence on parenteral nutrition or intravenous fluids (PN/IV) to maintain 
energy and fluid and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus height 
and crypt depth, dilation, and delayed intestinal transit. The main principle of management of 
SBS is to provide the minimal necessary parenteral support to maintain energy, fluid, and 
electrolyte homeostasis while maximizing enteral feeding to promote intestinal adaptation. In 
infants, rapid linear growth of the intestines during the first year of life dramatically 
complements the aforementioned adaptive responses. About 30% of infants who develop SBS 
during the neonatal period become independent of PN/IV requirements by 12 months of age, and 
an additional 10% wean off PN/IV support by 24 months of age. After this time, linear intestinal 
growth slows. About 60% of children with SBS are able to become independent of parenteral 
support within 5 years. (Khan et al. 2015; Squires et al. 2012)  Nevertheless, despite optimal 
medical management, many children remain dependent on PN/IV support.
Complications of long-term parenteral support include liver disease, catheter-related blood 
stream infections, central line-associated venous thrombosis and dwindling central venous 
access. Sepsis is the leading cause of death in these patients, and quality of life is poor. 
Accelerating the adaptive process is an urgent goal for all patients with SBS who are dependent 
on parenteral support.
For this reason, research in the pediatric arena is focused on children with PN/IV-dependent 
SBS. Given intestinal adaption in younger children, the unmet medical need is the greatest in 
children who are 1 year of age and older. It is highly unlikely that children with less than 10% of 
the expected length of small intestine reach enteral independence. These subjects reach a plateau 
in their ability to advance oral/enteral feeds or decrease PN/IV support (ie, are “stuck”) and are 
not expected to achieve spontaneous adaptation. Subjects who have not progressed to full enteral 
adaptation by 12 months after their intestinal insults are very unlikely to demonstrate 
spontaneous improvement in their enteral function. (Sigalet et al. 2011)
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide-2 (GLP-2), which is secreted from L-type 
enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
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There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS. In the US and Europe, a GLP-2 analog called teduglutide is approved for the treatment 
of SBS in adult patients who are dependent on PN/IV support. 
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 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. (Thymann et al. 2014; 
Tappenden et al. 2013)
Clinical Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries. Two 
completed adult studies (CL0600-004 and its extension, CL0600-005) evaluated safety and 
tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were dependent 
on parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, 
placebo-controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, 
assessed the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was 
a statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study. At week 24, the weekly reduction of PN/IV 
volume was similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, 
assessed the long-term safety of teduglutide and the proportion of responders in the CL0600-004 
study that maintained their response at the end of a further 28 weeks of treatment. The extension 
study also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in 
PN/IV. Seventy-five percent of the subjects who previously responded to teduglutide treatment 
in Study CL0600-004 maintained this response or experienced further improved benefit from 
teduglutide treatment. More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. Most of the adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus 
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13/43 subjects [30.2%], respectively). 
This difference was clinically and statistically significant in both the intent-to-treat (ITT) 
(p=0.002) and per-protocol (p < 0.001) populations. Generally, the incidence of 
treatment-emergent AEs was distributed similarly across all treatment groups. The 
treatment-emergent AEs with a higher incidence in the teduglutide group were mainly of GI 
origin. A long-term, open-label extension study (CL0600-021) assessed safety and efficacy for 
up to 24 additional months (ie, up to 30 months of exposure for subjects who received 
teduglutide in Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in 
Study CL0600-020 and entered Study CL0600-021 completed a total of 30 months of treatment 
with teduglutide. Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral 
support resulting in a PN/IV volume reduction of 7.55 L/week, corresponding to a mean 
reduction of 65.6% relative to baseline prior to exposure to teduglutide at the beginning of 
Study CL0600-020. PN/IV use was reduced by at least 1 day per week in 21 of 30 subjects 
(70%) who completed 30 months of treatment. Of the 39 subjects who entered 
Study CL0600-021 after receiving placebo in Study CL0600-020, 29 completed 24 months of 
treatment with teduglutide. The mean reduction in PN/IV volume was 3.11 L/week from baseline 
at the start of Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support. Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support.
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU countries. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts. 
There were no deaths during the study and no treatment-emergent AEs related to teduglutide 
were reported. No discontinuations from study were due to AEs. 
Additional information is provided in the investigator’s brochure.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Clinical Study 
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014. 
Based on national surveys, it is estimated that the number of subjects with SBS who are 
dependent on parenteral nutrition/intravenous fluid (PN/IV) is less than 1000 in Japan. 
(Takagi et al. 1995; Takehara 2001; Kitajima et al. 2013) Among the 195 SBS subjects in the 
2011 survey, 99 (51%) developed SBS at <1 years old. Early intervention could potentially 
improve intestinal adaptation and decrease the need for parenteral support in these patients.
The current study proposes to investigate the safe and appropriate use of teduglutide in the 
Japanese pediatric population for the purpose of providing pharmacokinetic, pharmacodynamic, 
and safety data. This protocol was developed similarly to the planned EU/US study, 
TED-C14-006, A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects through 17 Years of Age, with 
Short Bowel Syndrome who are Dependent on Parenteral Support. The TED-C14-006 protocol 
was developed with input from expert advisors from intestinal rehabilitation centers who offered 
advice on the most appropriate use of teduglutide in pediatric patients. The teduglutide dose of 
0.05 mg/kg daily is supported by results from the completed 12-week pediatric study. 
Teduglutide is approved for adult use in the US and EU at a dose of 0.05 mg/kg SC once daily. 
The completed 12-week pediatric study (TED-C13-003, A 12-Week Pharmacokinetic, Safety, 
and Pharmacodynamic Study of Teduglutide in Pediatric Subjects Aged 1 Year through 
17 Years, with Short Bowel Syndrome who are Dependent on Parenteral Support) demonstrated 
that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk 
profile. In addition, population pharmacokinetics (PK) modeling and simulations were conducted 
to determine the effective dose to be used in pediatric subjects using data from 8 adult clinical 
studies including adult Phases 1, 2, and 3 studies as well as the pediatric study (TED-C13-003); 
they suggested that the dose in pediatric subjects is likely to be the same as the dose in adults. 
(O'Keefe et al. 2006) The duration of teduglutide treatment in study SHP633-302 mirrors that of 
the TED-C14-006 study, consisting of 24 weeks of teduglutide treatment, followed by a 4-week 
follow-up period.
The aim of teduglutide treatment is to increase absorptive capacity in order to yield decreases in 
parenteral support. In addition, the experts anticipated that there would be several direct benefits 
from decreased parenteral support and advances in enteral feeds, including less exposure to 
PN/IV constituents, less central line manipulation with lower risk of infection, and more time to 
focus on oral rehabilitation strategies.
2.2
Objective(s) 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics (PD), and PK of teduglutide in pediatric subjects (1 year through 15 years of 
age) with SBS who are dependent on parenteral support. See Sections 9.8 and 9.10.1 for further 
details of the endpoints being measured, and Section 9.9 for safety variables.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of
teduglutide. All subjects will be screened for a minimum of 2 weeks prior to start of treatment to 
verify the requirements for nutritional support for each subject and to ensure adherence to 
eligibility parameters. Attempts should be made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks (weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, 
and 12). For the remainder of the treatment period, visits at the sites will be conducted every 
3 weeks (at weeks 15, 18, 21, and 24). Scheduled telephone contacts will be made on all other 
weeks during the treatment period. At all site visits and during telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed. The end of study 
(EOS) visit will be scheduled at week 28, 4 weeks following end of treatment (EOT). Weekly 
telephone contact will be made during the interim weeks from EOT to EOS to monitor safety and 
any changes in nutritional support. The Study Schedules (Table 1 and Table 2) are displayed at 
the beginning of this protocol.
A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as 
an unscheduled visit.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines and weaning algorithms (developed with SBS expert input and 
provided in Appendix 2 and Appendix 3, respectively) for decisions regarding PN/IV support 
reduction and advances in enteral feeds based on weight gain, urine, and stool output in the 
setting of clinical stability. Any departure from the nutritional support adjustment guidelines and 
weaning algorithms will not constitute a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post EOT 
for another antibody sample. If the subjects continue to have positive/specific antibodies at 
3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) which 
will convene approximately every 3 months during the active study period, based on subject 
enrollment.
All subjects who complete the study may participate in a long term extension study in which 
eligible subjects could receive teduglutide.
A schematic representation of the study design is displayed in Figure 1.
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Figure 1
Study Diagram
EOS=end of study; EOT=end of treatment 
3.2
Study Duration
There will be, at a minimum, a 2-week screening period from the time of the screening visit to 
the baseline visit, followed by 24 weeks of treatment. Attempts should be made to limit the 
screening period to 4 weeks. The EOS visit will be scheduled at week 28, 4 weeks after the EOT 
visit (week 24). 
The start of the clinical phase is defined as first subject consented. The end of the clinical phase 
is defined as the last visit of the last subject.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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4
STUDY POPULATION 
Approximately 5 pediatric Japanese subjects, male and female children and adolescents aged 
1 year through 15 years, will be enrolled. 
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Informed consent by a parent or guardian prior to any study-related procedures
2. When applicable, informed assent (as deemed appropriate by the Institutional Review Board) 
by the subject prior to any study-related procedures 
3. Male or female child or adolescent aged 1 year through 15 years 
4. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
5. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs
6. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment of sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
7. Sexually active female subjects of childbearing potential must use medically acceptable 
methods of birth control during and for 4 weeks following the last dose of investigational 
product
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
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7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease or congenital heart disease  or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic GLP-2 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
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22. Parent(s)/guardian(s) and/or subjects who are not capable of understanding or not willing to 
adhere to the study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results. Examples of potential disease states/illnesses that may be excluded are listed in 
Table 3.
Table 3
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in the GI tract 
identified by upper GI series, biopsy or polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug abuse within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease
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4.3
Reproductive Potential 
Sexually active females of childbearing potential must be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 4 weeks following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception if they become sexually active during the 
period of the study and 4 weeks following the last dose of investigational product. 
Female children and adolescent subjects should be either:
Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or
Females of childbearing potential with a negative serum β-HCG pregnancy test at the screening 
visit (visit 1) and a negative urine β-HCG pregnancy test prior to enrollment. Females of 
childbearing potential must agree to abstain from sexual activity (ie, true abstinence) that could 
result in pregnancy or agree to use medically acceptable methods of contraception at all times 
during the study and 4 weeks following the last dose of investigational product. 
Note: True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).
4.4
Discontinuation of Subjects
4.4.1
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to further treatment. However, a discussion should be 
held by the investigator and the Shire medical monitor or designee prior to the subject 
discontinuing or withdrawing. 
4.4.2
Reasons for Discontinuation

Reasons for discontinuation may include but are not limited to:

Adverse event

Death

Failure to meet enrollment criteria

Lost to follow-up

Non-compliance with investigational product

Physician decision

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Technical problems

Withdrawal by parent/guardian
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
Withdrawal by subject
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 8.1. 
To the extent possible, all examinations scheduled for the EOT evaluation must be performed on 
all subjects who participate even if they do not complete the study according to the protocol 
(ie, early termination). Any subject who discontinues treatment prematurely will be asked to 
return 4 weeks later for the EOS visit and will be contacted weekly for wellness checks during 
the interim period between EOT and EOS.
4.4.3
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 timepoint prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including non-prescription herbal treatments, vitamins, invasive and 
diagnostic procedures) received within 14 days prior to the screening visit (visit 1) and through 
the end of study (ie, including the protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 14 days of the first dose of investigational 
product, but discontinued before the first dose of investigational product. 
5.2
Concomitant Treatment
Concomitant medications are those that continue after the start of investigational product or are 
newly introduced after the start of treatment through the end of study. In all instances the start 
date of prior and concomitant therapies must be recorded to the extent possible.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
Changes in any medication and/or dosage will be recorded on the eCRF. See also nutritional 
support in Section 7.2.15.2.
5.3
Prohibited Treatment
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The following prior therapies are excluded within the timeframes noted (see Section 4.2).
Prior Therapy
Time Restriction Prior 
to Screening
Native/synthetic glucagon-like peptide-2
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy used to treat inflammatory bowel disease (eg, antitumor 
necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Teduglutide for subcutaneous (SC) injection is provided in 3 mL vials containing 5 mg or 
1.25 mg teduglutide as a lyophilized powder that must be reconstituted using 0.5 mL with sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the investigator’s brochure.
6.1.1
Blinding of the Treatment Assignment
Not applicable.
6.1.2
Administration of Investigational Product
A dose of 0.05 mg/kg/day of teduglutide will be administered once daily to the subjects for 
24 weeks. The dose calculation will be based on body weight measured at the baseline visit 
(visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with the Shire medical monitor or designee.
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
Each day, the injection site should be rotated.  The site of administration (arm, thigh, abdomen) 
of the first teduglutide dose must be specified and recorded in the eCRF.
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.  Detailed instructions for reconstitution and injection of the investigational product can be 
found in the Instructions for Use.
The subject should be dosed at approximately the same time each day. If a dose is delayed, that 
day’s dose should be administered as soon as possible, but consecutive doses should be separated 
by at least 12 hours.
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6.1.2.1
Administration by Parent/Guardian
The first dose of teduglutide will be administered by a study physician and the subject is
observed for possible hypersensitivity reactions for at least 4 hours during their initial dosing 
visit. 
The processes for training the parent/guardian to administer teduglutide and for providing 
oversight of study drug administration are described in the Site Training Guide.  Before a 
parent/guardian is permitted to administer teduglutide, the study physician must observe the 
parent/guardian administering the study drug at least twice in compliance with the teduglutide 
administration checklist. The checklist is included as an Appendix to the Site Training Guide. 
After the study physician certifies that the parent/guardian can safely administer the study drug, 
subsequent doses may be administered by the parent/guardian at home without direct supervision 
by the physician.  However, at selected study visits during the dosing period (refer to Table 1), 
administration of the study drug must be performed under direct supervision by the study 
physician, and the teduglutide administration checklist must be completed again.  This ensures 
that the parent/guardian continues to administer the study drug correctly and safely throughout 
the dosing period.
If at any time a study physician suspects that the parent/guardian is no longer capable of 
administering the study drug safely and accurately, the parent/guardian should be re-assessed by 
a study physician using the teduglutide administration checklist.  If the parent/guardian is 
deemed unable to administer the study drug, dosing must be performed by a study physician until 
the parent/guardian is re-trained and proficiency is confirmed using the teduglutide 
administration checklist.  
Eligibility for teduglutide to be administered by a parent/guardian will be judged by a study 
physician using the following criteria.  Refer to the checklist included as an appendix to the Site 
Training Guide.
Criteria to Initiate Teduglutide Administration by the Parent/Guardian:

The subject’s condition is stable.

The parent/guardian has been sufficiently trained and is able to administer teduglutide 
in compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Parent/Guardian:

The parent/guardian is unable to administer teduglutide in compliance with the 
checklist.

The subject’s condition has deteriorated such that the study physician assesses it is 
inappropriate for the subject to have teduglutide administered by their 
parent/guardian. In addition to discontinuing administration of teduglutide by the 
parent/guardian, if a subject sustains an adverse drug reaction where the symptoms 
are considered intolerable, dose interruption or study drug discontinuation should be 
considered (see Section 8.4). 

In the study physician’s judgment, it is inappropriate for the parent/guardian to
continue administration of the study drug for any other reason.
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6.1.3
Allocation of Subjects to Treatment 
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day as described in 
Section 6.1.2. Subject numbers are assigned to all subjects as consent/assent to take part in the 
study is provided. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. These 
numbers will be used to identify the subjects throughout the study period. Once a number/unique 
identifier has been assigned, that number must not be used again if, for example, a subject is 
withdrawn from the study. If a unique identifier is allocated incorrectly, the study monitor must 
be notified as soon as the error is discovered.
6.2
Labeling, Packaging, and Storage
6.2.1
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 Practices.
6.2.2
Storage
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 and 8oC 
until dispensed to a subject. The pre-filled sterile water for injection syringes will be stored at a 
temperature between 2 and 25°C. Once dispensed/supplied to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25oC). Parent/guardian will be instructed to keep the subject’s investigational product and sterile 
water diluent at controlled room temperature. If there are concerns that the controlled room 
temperature cannot be maintained, the investigational product may be refrigerated.
6.3
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the study visits at which the subject is required to be at 
the clinic. Each investigational product kit is sufficient for a treatment period of 1 week and 
enough kits will be supplied to cover the period until the next planned study visit. Additional 
study kits will be provided as necessary.
Each subject will be given the investigational product according to his/her treatment assignment. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. All dispensed medication will be documented on the eCRFs and/or other 
investigational product record. The investigator is responsible for assuring the retrieval of all 
study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects. 
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.
See the Pharmacy Manual for additional information.
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6.4
Treatment Compliance
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by reviewing the subject diaries and asking the subject,
the subject’s parent or guardian, or the study site staff if they have administered the 
investigational product according to instructions. If any doses have been missed, the reason for 
missed dose should be documented in the subject’s source documentation including, as 
applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc. 
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. Subjects falling outside of these parameters will not be included in the per-protocol 
efficacy analyses (see Section 9.6).
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7
STUDY PROCEDURES
7.1
Study Schedule
Subject evaluations will be performed during the indicated days and weeks of the study as 
provided in the Study Schedules (Table 1 and Table 2). 
All data collected are to be recorded on the appropriate eCRF.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1.1
Screening
All subjects’ parents/guardians must sign an informed consent form and, if applicable, subjects 
must sign an informed assent form prior to initiation of any study-related procedure. All subjects 
will be screened for a minimum of 2 weeks. Attempts should be made to limit the screening 
period to 4 weeks.
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigation product. 
At the discretion of the investigator, subjects who fail screening may be re-screened one time 
with prior sponsor approval. In the event of re-screening, a new subject number will be assigned 
to the subject and the subject will also be re-consented.
7.1.2
Treatment Period
Subjects who meet all eligibility criteria at screening, and eligibility criteria are confirmed at 
visit 2/baseline, will be enrolled in the study and will receive the first dose of investigational 
product at the baseline visit (visit 2). Subjects will enter a 24-week treatment period consisting of 
either visits or scheduled weekly telephone contacts as outlined in the Section 3.1.
7.1.3
Follow-up Period
During the 4-week follow-up period, weekly telephone visits will be conducted on week 25 to 
week 27 followed by the EOS visit (week 28). Similar to assessments performed during the 
treatment period, phone visits during follow-up will include review of intake diaries, and 
adjustment of nutritional support as needed (see Section 3.1). Procedures to be performed at the 
EOS visit (week 28) are specified in the Study Schedules (Table 1 and Table 2); subjects will be 
queried on serious adverse events (SAEs), AEs, and concomitant treatments, and all AEs and 
SAEs that are not resolved at the time of this visit will be followed to closure (see Section 8.1).
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7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (and, when 
applicable, informed assent) must be obtained from the subject’s parent(s) or guardian(s) and 
from the subject (if applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s guardian(s) by the investigator or 
designee in accordance with the guidelines described in Section 10.3.1. Documentation and 
filing of informed consent documents should be completed according to Section 10.2.
7.2.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria by 
the investigator or designee. Subjects who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the subject’s ineligibility for the study will 
be documented.
7.2.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at 
baseline by the investigator or designee on the basis of review of the study entrance criteria.
7.2.4
Demographics and Other Baseline Characteristics
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy

GI-specific symptoms history (Section 7.2.15.1)

Physical examination, including body weight, height (or length), and head circumference (up 
to 36 months of age), and trends on growth charts

Vital signs including temperature, heart rate, and blood pressure

Prior medications (medications used within 14 days prior to screening and discontinued prior 
to the first dose of investigational product), including drug name, dose, route, reason for use, 
and therapy dates. Medications used during the treatment period (after the first dose of 
investigational product) will be recorded as concomitant medications.

Electrocardiogram (ECG) (12-lead) variables include general findings (normal/ abnormal, 
not clinically significant/ abnormal, clinically significant). The cause of any clinically 
significant ECG will be specified.
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
Laboratory test results: biochemistry, hematology, coagulation, and urinalysis

Plasma citrulline levels

Presence of antibodies to teduglutide and titer level, if present

Gastrointestinal imaging/testing (upper GI series with small bowel follow-through 
[UGI/SBFT], abdominal ultrasound, colonoscopy or sigmoidoscopy, fecal occult blood)

Pregnancy testing for females of childbearing potential

Nutritional support prescriptions (eg, PN/IV and enteral nutrition [EN] volume and calories, 
PN/IV hours per day and days per week) (Section 7.2.15.2)

Nutritional support diary data (Section 7.2.15.3)
7.2.5
Pharmacokinetic Assessments
Pharmacokinetic assessments are listed in Section 9.10.1. 
Blood samples for teduglutide concentrations will be collected at the baseline and week 4 visits. 
If blood samples are not/cannot be collected at week 4, the uncollected samples can be collected 
during any future site visit while the subject is still on investigational product. A schedule of PK 
sample collection is provided in Table 4. Instructions for sample collection and handling are 
included in the Laboratory Manual.
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing
Study week
Baseline
Week 4
Visit Number
2
6
Hour
0a
1
6
0a
2
4
a Prior to investigational product administration
The timepoints indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these timepoints may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

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 (at the week 4 draw).

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes

6-hour postdose draw: ±30 minutes
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At PK timepoints, the date and time of investigational product administration and blood 
collection must be recorded on the eCRF.
7.2.6
Physical Examination (Including Height and Weight)
Physical examinations will be performed, and body weight, height (or length), and head 
circumference (up to 36 months of age) measured according to the Study Schedules (Table 1 and 
Table 2).
Physical examinations will be performed by the investigator during the study 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.
Subjects should be weighed on the same scale at each study visit. Height (or length [cm]) and 
head circumference (for subjects ≤36 months of age[cm]) will be measured at selected visits.
Body mass index (BMI) and z-scores for weight, height (or length), head circumference, and 
BMI will be calculated by the sponsor. 
7.2.7
Vital Signs
Vital signs will be measured according to the Study Schedules (Table 1 and Table 2). 
Measurements will include body temperature (°C), heart rate (beats per minute), and systolic and 
diastolic blood pressure (mmHg). 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.
7.2.8
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing according to the Study Schedules (Table 1 and Table 2). Subjects should be in a seated or 
supine position during blood collection.
Laboratory collections required at intervals that do not coincide with site visits (safety laboratory 
assessments eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at 
the investigational site. 
Clinical laboratory tests will include the following (see Table 5):
Table 5
List of Laboratory Tests
Hematology:
Hematocrit 
Hemoglobin 
Platelet count
Biochemistry:
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
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Table 5
List of Laboratory Tests
Red blood cell (RBC) count 
RBC morphology, if needed
White blood cell count with differential
Coagulation:
Prothrombin time/International  normalized ratio 
will be measured in all subjects at screening and 
subsequently if confirmed drug-induced liver 
injury (DILI) is suspected (Section 8.4.2)
Urinalysis: 
Blood
Glucose
Leucocytes
Microscopic analysis
pH 
Protein
Specific gravity
Pregnancy tests (females of childbearing 
potential):
Serum β-HCG (screening)
Urine β-HCG (all other visits)
Amylase
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total, direct, and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
C-reactive protein 
Creatinine
Estimated glomerular filtration rate 
(Schwartz formula)
Gamma-glutamyl transferase 
Glucose
Lipase
Magnesium
Phosphorus
Potassium 
Sodium 
Triglycerides
Uric acid
For children in diapers, urine specimen collection should be attempted as part of the safety lab 
assessments, but lack of urinalysis will not constitute a protocol deviation.
7.2.9
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass. Blood samples will 
be collected 2 to 4 hours postprandial, whenever possible, at the timepoints specified in the 
Study Schedules (Table 1 and Table 2). Samples may be drawn from a central line or peripheral 
access and processed according to instructions in the Laboratory Manual. 
7.2.10 Antibody Assessments
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the baseline visit (day 0) and at least 14 hours after the previous 
dose at the EOT visit (week 24 or early termination); samples may be drawn from a central line 
or peripheral access. One additional sample will be collected at the EOS 4 weeks after the EOT 
(ie, week 28 or EOS). 
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If a blood sample tests positive for anti-teduglutide antibodies at week 28 or EOS, then the 
subject will be retested 3 months after EOT. If that sample tests positive, then the subject will be 
retested 6 months after EOT.
7.2.11 Pregnancy Testing
Any female subject of childbearing potential (Section 4.3) must have negative pregnancy tests to 
enroll or continue in the study. Pregnancy tests will be performed at screening (serum β-HCG 
testing) and at all site visits (urine β-HCG testing). 
7.2.12 Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study.
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than one blood assessment 
is to be done at the same timepoint, the assessments should be combined if they require the same 
type of tube.
7.2.13 Electrocardiogram
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) 
as indicated in the Study Schedules (Table 1 and Table 2). Electrocardiogram recordings will be 
read locally by an experienced physician. Results (normal; abnormal, not clinically significant; 
and abnormal, clinically significant with a description of the abnormality) will be recorded on 
the eCRF. 
7.2.14 Gastrointestinal-specific Testing
Gastrointestinal testing will be performed as needed for all subjects during the screening period, 
as indicated in sections 7.2.14.1 to 7.2.14.4. Follow-up testing will be performed as needed 
according to the guidelines noted in sections 7.2.14.1 to 7.2.14.4 and the Study Schedules (Table 
1 and Table 2).
7.2.14.1
Upper Gastrointestinal Series with Contrast
An UGI/SBFT will be performed following the ingestion of barium contrast material during the 
screening period. Results from procedures performed within 6 months prior to visit 1 will also be 
acceptable.
7.2.14.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to visit 1 will also be acceptable.
7.2.14.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, week 12, and week 24 (EOT). 
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Subjects with positive fecal occult blood testing results at screening or at week 24 for whom a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy. Subjects with positive fecal occult blood testing results at week 12 for which a 
cause is not identified by a physical examination will be discussed with the Shire medical 
monitor or designee. If clinically indicated, an esophagogastroduodenoscopy (EGD) may also be 
performed with any colonoscopy or sigmoidoscopy.
Subjects with negative endoscopy findings at screening may enroll in the study.
Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with Shire’s medical monitor or designee, the subject is 
considered appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with Shire’s medical monitor or designee, the 
subject is considered inappropriate to be enrolled in the study.
7.2.14.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy or sigmoidoscopy at screening. 
If the fecal occult blood testing is negative at screening and the procedure was performed within 
1 year before the screening visit (visit 1), then those prior results are acceptable for the screening 
assessment.
Children younger than 12 years will undergo the procedure if they test positive for fecal occult 
blood at screening and the cause is not identified by physical examination (see Section 7.2.14.3).
Requirements for colonoscopy or sigmoidoscopy in response to positive fecal occult blood 
testing at weeks 12 or 24 are presented in Section 7.2.14.3.
7.2.15 Other Study Procedures
7.2.15.1
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/guaridan
representative in a GI-specific symptoms history diary on a daily basis. At the baseline visit, the 
investigator will review the GI-symptoms diary and summarize the findings.
7.2.15.2
Nutritional Support
Nutritional support includes PN/IV and EN. Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status, 
and safety laboratory results. Guidelines for nutritional support management and weaning 
algorithms are provided in Appendix 2 and Appendix 3, respectively. 
Intake diaries will be used to collect and evaluate each subject’s nutritional support. 
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7.2.15.3
Diaries
The subject/parent/guardian/study site staff will complete the appropriate fields of the PN/IV and 
EN (formula) sections of the intake diary.
Intake diary:  The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:
PN/IV volume and infusion duration
EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
Output diary:  Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every site visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc. The subject or parent will 
perform dipstick specific gravity tests on the first urine produced after the daily 
infusions of PN/IV support.

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first 
void after the daily PN/IV infusion to measure specific gravity.

Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency 
using the Bristol Stool Form Scale (see output diary)

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine 
and stool) as stool output and score the stool consistency using the Bristol Stool 
Form Scale (see output diary). Stool volume will be calculated using the formula: 
1 g (scale weight) = 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
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8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 3.2. This includes events occurring during the screening phase 
of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Note that the severity of AEs listed in Table 6 that may lead to dose interruption based on known 
risks of teduglutide will also be evaluated using the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria (Section 8.4.1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
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, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the 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 end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment 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, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 3.2.
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 SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) 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 the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol as well as the Shire 
Investigational and Marketed Products Pregnancy Report Form. The test date of the first positive 
serum/urine β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Administration of a dose greater than the allocated dose of investigational 
product or at a frequency greater than the dosing interval specified by the protocol. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/guardian.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.
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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
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 
e-mail address can be found on the form (sent under separate cover). 
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed 
consent/assent is signed until the defined follow-up period stated in Section 3.2 and must be 
reported to Quintiles Transnational Japan K.K within 24 hours of the first awareness of the 
event. 
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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 Quintiles 
Transnational Japan K.K within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent form, or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
Quintiles Transnational Japan K.K is responsible for notifying the relevant regulatory 
authorities/central institutional review boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs. In addition the sponsor and/or designee is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the 
teduglutide program. 
The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
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The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
For AEs of special interest, Quintiles Transnational Japan K.K Quintiles Transnational Japan 
K.K must be informed within 24 hours of first awareness as per the SAE notification instructions 
described in Section 8.2.2 even if the event does not fulfill seriousness criterion.
8.4
Dose Interruption of Individual Subjects 
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
Investigational product must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related to 
the investigational product. This does not include the presence of anti-teduglutide antibodies, 
mild injection site reactions or mild symptoms that according to the investigator do not pose 
a significant risk to the subject.

An AE listed in Table 6 that is of NCI CTCAE severity Grade 3 or 4 and considered to be 
related to the investigational product administration (see Section 8.4.1)

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The investigational product may be discontinued if the subject experiences an AE listed in Table 
6 that is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with 
Shire’s medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the DMC should be guided by the descriptions of Grade 3 and 4 events, as they 
relate to identified risks associated with the administration of teduglutide (see Table 6).
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening  consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent 
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or 
hospitalization indicated; nonemergent 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent 
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (total bilirubin >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification laboratory assessments and an 
inquiry should be made as to the presence of clinical symptoms consistent with new liver injury. 
The subject should be followed closely to determine the trajectory of the laboratory 
abnormalities and to evaluate the cause of liver injury. This evaluation may include, as clinically 
indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A immunoglobulin M [IgM], 
hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, Epstein-Barr virus 
antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (anti-nuclear, 
anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), intestinal failure 
associated liver disease, cardiovascular causes such as ischemic hepatitis, and concomitant 
hepatotoxic treatments.
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Additional evaluations may be performed at the discretion of the investigator in consultation 
with Shire medical monitor or designee.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
investigational product.
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8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

At least 2 subjects develop the same event listed in Table 6 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 6 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying disease 
process.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator or investigators’ authorized site personnel must enter the information required 
by the protocol in the eCRF. A study monitor will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the eCRF will be addressed by 
the investigator or qualified site personnel. When a data discrepancy warrants correction, the 
correction will be made by the investigator or authorized site personnel. The investigator must 
verify that all data entries in the eCRF are accurate and correct. Original diary data should be 
entered into the eCRF and take precedence over data collected over the phone. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. Once a subject is enrolled, it is expected that the investigator or authorized site 
personnel will complete the eCRF entry in a timely manner following the subject’s visit.
9.2
Clinical Data Management
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US Food and Drug Administration (FDA) 21 CFR Part 11 Guidance. The 
clinical trial database will include an audit trail to document any evidence of data processing or 
activity on each data field by each user. 
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will 
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Pharmacovigilance and Risk Management database.
9.3
Statistical Analysis Process
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.
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Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
All statistical analyses will be performed using SAS®.
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design.
9.4.1
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by Shire, independent contractors hired by Shire, or members of regulatory 
agencies. The DMC may make recommendations to Shire regarding stopping, modifying or 
continuing the study; however, Shire will have the final responsibility to determine whether the 
study should be modified or temporarily or permanently stopped. 
Safety and tolerability results will be evaluated by a DMC which will convene approximately 
every 3 months during the active study period (date of the first subject’s first dose to date of the 
last subject’s last dose), based on subject enrollment. The DMC review will include all 
cumulative safety data from study assessment through the end of each review period.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation.
9.6
Study Population
Subjects are considered enrolled in the study when they meet all eligibility criteria at screening 
and eligibility criteria are confirmed at visit 2/baseline.
The ITT population is defined as any subjects who were enrolled into the study. The safety 
population is defined as the subset of ITT with subjects who received at least 1 administration of 
investigational product with any safety follow-up. The primary population analyzed for 
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efficacy/PD will be the ITT population. 
An additional per-protocol population analysis will also be performed as secondary/sensitivity 
analysis. The per-protocol population is defined as the subset of subjects in the ITT population 
without a major protocol deviation. Details will be prospectively defined in the final SAP prior to 
database lock.
The PK analysis population is defined as all subjects in the safety analysis population for whom 
the primary PK data are considered sufficient and interpretable.
9.7
Demographics and Baseline Characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories) will be presented, as appropriate, to 
summarize the demographic and baseline variables.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized. 
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with specific histories 
will be summarized by system organ class and preferred term.
9.8
Efficacy/Pharmacodynamic Analyses
The efficacy/PD endpoints include: 

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) 
compared to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, to 
week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
No formal statistical test will be performed due the limited sample size.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
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9.9
Safety Analyses
The safety and tolerability variables include:

Adverse events, including those pertaining to GI symptoms

Body weight, height (or length), head circumference (up to 36 months of age), and trends on 
growth charts

Vital signs, including temperature, heart rate, blood pressure 

Electrocardiograms

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis) including the 
following lab tests at all site visits and interim safety labs to detect hepatotoxicity signals:  
AST, ALT, ALP, and bilirubin

Urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal 
occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment-emergent AEs will be summarized by 
system organ class and preferred term. The number and percentage of subjects with AEs, SAEs, 
AEs that lead to discontinuation, investigational product-related AEs (determined by the 
investigator), and AEs that resulted in a fatal outcome will be summarized. AEs will also be 
summarized with regard to intensity and relationship to investigational product. For AEs of 
special interest, the CTCAE grading system will be used as described in Section 8.4.1.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies.
9.10
Other Analyses
9.10.1 Pharmacokinetic Analyses
The following PK parameters will be estimated based on measured teduglutide plasma 
concentrations using a population PK modeling approach:

Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUC0-t)
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
AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Cmax at steady state (Cmax,ss)

Minimum plasma concentration at steady state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics for PK parameters (mean, median, standard deviation, minimum and 
maximum values, geometric mean) will be calculated.
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10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’s Responsibilities
10.1.1 Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee ensures that local regulatory authority requirements are met before the 
start of the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior to 
release of investigational product for shipment to the site.
10.1.2 Public Posting of Study Information
The sponsor or designee is responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries may include participating 
investigators’ names and contact information.
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. 
10.1.4 Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
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10.2
Investigator’s Responsibilities
10.2.1 Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor or designee before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent/assent, inform them of the subject’s participation in the study.
10.2.2 Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will 
promptly inform the sponsor and the IRB/EC and provide them with a detailed written 
explanation. The investigator will also return all investigational product, containers, and other 
study materials to the sponsor. Upon study completion, the investigator will provide the 
sponsor, IRB/EC, and regulatory agency with final reports and summaries as required by 
international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is 
provided at all phases during the study, may be done by the sponsor, applicable contract 
research organization, investigator, or for multicenter studies, the coordinating principal 
investigator according to national provisions and will be documented in the investigator 
agreement.
10.2.3 Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms will be supplied by the sponsor or designee and should be handled 
in accordance with instructions from the sponsor.
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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 solely onto the eCRF.
All data transmitted to the sponsor or designee must be endorsed by the investigator. The study 
monitor will verify the contents against the source data per the monitoring plan. If the data are 
unclear or contradictory, queries will be sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to subject’s 
medical file, subject diaries, and original clinical laboratory reports, and imaging reports. All key 
data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the 
Pharmaceuticals and Medical Devices Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator receives from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1 Informed Consent
It is the responsibility of the investigator or designee to obtain written informed consent from 
all subjects or parents/guardians, and assent from subjects where applicable, prior to any study-
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related procedures including screening assessments. All consent and assent documentation must 
be in accordance with applicable regulations and GCP. Each subject or the subject’s parent or 
guardian, as applicable, is requested to sign and date the informed consent form/assent, or a 
certified translation if applicable, after the subject has received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent/assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent or guardian, as applicable. This document requires translation into the local 
language. Signed consent/assent forms must remain in each subject’s study file and must be 
available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/guardian of the safe, responsible storage and administration of investigational 
product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form and assent 
form where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2 Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent 
document (approved by the sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. Responsibility for coordinating with IRBs/ECs is defined in the 
investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor or designee has received
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies 
this can be done by the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
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10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) 
which gave approval for the study to proceed. The sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11 LIST OF REFERENCES
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Kitajima, M., Shamizu, M., Wakabayashi, G., Hoshino, K., Tanabe, M. & Kawachi, S. 2013. 
Current Issues in Liver and Small Bowel Transplantation, Springer Science & Business 
Media.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D., Boctor, D., Brindle, M., Lam, V. & Robertson, M. 2011. Elements of successful 
intestinal rehabilitation. J Pediatr Surg, 46, 150-6.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Takagi, Y., Okada, A., Sato, T., Fukushima, T., Shirotani, N., Osawa, Y., Takeyama, H., 
Taniguchi, M., Takehara, H. & Mizote, H. 1995. Report on the first annual survey of 
home parenteral nutrition in Japan. Surg Today, 25, 193-201.
Takehara, H. 2001. Home parenteral nutrition for pediatric patients. Nihon Rinsho, 59 Suppl 5, 
848-51.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
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12 APPENDICES
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APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
18 Dec 2015
Global
Amendment 1
27 Apr 2016
Global
Amendment 2
06 Jun 2017
Global
Amendment 3
24 Jan 2018
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
06 Jun 2017
Global
Description of Change
Section(s) Affected by Change
The Pharmacovigilance SAE Reporting fax number and email address have 
been updated. A sentence has been removed from the emergency contact 
information to eliminate a redundancy with the information provided under 
the Pharmacovigilance SAE Reporting heading (Protocol Administrative 
Change Memo #2, dated 24 Aug 2016). The title of Andrew Grimm MD 
PhD is now Medical Director and his email address has been changed.
Protocol Signature Page 
Emergency Contact Information
Urine osmolality (Protocol Administrative Change Memo #1, dated 10 Aug 
2016) and urine sodium have been removed from the list of urinalysis 
parameters to be tested. Neither parameters are needed as safety parameters 
nor required for the decision to adjust a subject’s nutritional support. 
Table 5
Clarification that biological therapy prohibited during teduglutide treatment 
and within 6 months prior to the pretreatment visit refers to biological 
therapy used to treat inflammatory bowel disease.
Section 5.3
Clarification that subjects, and/or any designated person who will be 
administering the investigational product, will be trained on investigational 
product preparation and administration before the first dose of teduglutide 
or the implementation of any change in ancillary kit components.
Section 6.1.2
Language on contents of ancillary kits has been revised.
Section 6.2.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Age range for subjects has been specified. Subjects will be 1 year through 
15 years of age. 
Title page
Protocol signature page
Synopsis
Sections 4 and 4.1
Emergency contact information has been updated.
Emergency Contact Information
Sections 8.1.6, 8.2.2, 8.2.4 
Clarification that departing from the nutritional support adjustment 
guidelines and weaning algorithms in Appendix 2 and Appendix 3, 
respectively, will not constitute a protocol deviation. 
Synopsis
Section 3.1
Statement added that subjects who complete the study may participate in a 
long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Section 3.1
Inclusion and Exclusion criteria have been refined and clarified; there were 
no criteria added with the exception of the age of subject population which 
has been added as an inclusion criterion (was previously in introductory 
sentence).
Synopsis
Sections 4.1 and 4.2
Exclusion Criterion #11 has been updated to indicate that a subject would 
be excluded from the study if the subject had participated in a clinical study 
of experimental drug within 3 months or 5.5 half-lives of the experimental 
drug, whichever is longer.
Synopsis
Section 4.2
Efficacy/PD endpoints have been lumped together and clarified. The small 
population does not warrant primary versus secondary endpoints. The 
statistical method has been clarified.
Synopsis
Section 9.8
Safety assessments and statistical methods have been clarified. 
Synopsis
Section 9.9
Study schedule of events tables have been revised to reflect the changes to 
the protocol and for clarity.
Table 1
Table 2
Any phone contacts may be replaced with unscheduled site visits if 
necessary.
Table 1
Table 2
Section 3.1
Requirement added that female subjects of child-bearing potential undergo 
a serum-based pregnancy test at screening.
Table 1
Table 2
Sections 4.3, 7.2.8, 7.2.11
Definition of prior and concomitant medications has been expanded to 
include invasive and diagnostic procedures.
Table 1
Table 2
Section 5
Additional information on selection of teduglutide dosing regimen and 
duration in the study has been inserted.
Section 2.1
Frequency of Data Monitoring Committee meetings has been specified.
Sections 3.1 and 9.4.1
Definition of screening period has been clarified.
Section 3.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy for symptom control has been removed from 
the list of excluded disease and illness in Exclusion Criterion #24.
Section 4.2 (Table 3)
Definition of acceptable methods of contraception has been revised to 
reflect available methods in Japan.
Section 4.3
List of prohibited prior therapy has been revised to remove experimental 
antibody treatment, as it is now included in the revised exclusion 
criterion #11.
Section 5.3
Requirement that teduglutide should be administered in the morning has 
been removed.
Section 6.2
Language on labeling, packaging, and drug accountability has been 
clarified.
Sections 6.3 and 6.4
Reviewing subject diaries has been included in the subject compliance with 
dosing check. Clarification that attempts should be made by the investigator 
to contact the sponsor or designee prior to dose interruption has been 
added.
Section 6.5
Requirement has been added that subjects who are re-screened must be re-
consented.
Section 7.1.1
Timeframe for a subject to be considered enrolled in the study has been 
clarified.
Sections 7.1.2 and 9.6
Demographics and other baseline characteristics have been clarified.
Section 7.2.4
Windows for PK blood collection have been extended; possibility to collect 
week 4 timepoint at any future visit if needed has been added.
Section 7.2.5
PT/INR testing has been added at screening and subsequently if confirmed 
drug-induced liver injury (DILI) is suspected thereafter.
Table 1
Table 2
Section 7.2.8
For children in diapers, urine specimen collection should be attempted as 
part of the safety lab assessments, but lack of urinalysis will not constitute a 
protocol deviation.
Table 1
Table 2
Section 7.2.8
Timeframe of follow-up for subjects with blood samples testing positive for 
anti-teduglutide antibodies at week 28 or EOS has been clarified.
Synopsis
Table 1
Table 2
Section 7.2.10
Need for a subject with a positive fecal occult blood testing at week 12 
without a readily identifiable cause by physical examination to undergo a 
colonoscopy or sigmoidoscopy is now open to discussion with the Shire 
medical monitor or designee.
Table 1
Table 2
Section 7.2.14.3
Need for children younger than 12 years to undergo a colonoscopy or 
sigmoidoscopy if they test positive for fecal occult blood at screening and 
the cause is not identified by physical examination has been specified.
Section 7.2.14.4
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
GI symptoms history worksheet has been renamed GI-specific symptoms 
history diary, and details on recording and reviewing symptoms have been 
added. 
Table 1
Table 2
Section 7.2.15.1
“Other nutrition (regular diet and drink)” has been removed from the Intake 
diary.
Section 7.2.15.2
Output diary data collection will continue to occur over a 48-hour period of 
PN/IV and EN stability before every site visit. Between site visits, the 
output diary collection will only be required within 1 week of 
implementing a change in the PN/IV prescription.
Table 1
Table 2
Section 7.2.15.3
Severity categorization has been updated to specify that the severity of AEs 
listed in Table 6 that may lead to dose interruption based on known risks of 
teduglutide will also be evaluated using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grading criteria.
Section 8.1.1
Definition of an overdose to teduglutide has been revised.
Section 8.1.7
Adverse events of special interest have been redefined and procedures for 
reporting them have been added.
Section 8.3
More information has been provided on criteria for dose interruption of 
individual subjects. Dose discontinuation has been made absolute for an AE 
known to be a risk associated with teduglutide administration (Table 6) that 
is of NCI CTCAE severity ≥Grade 3 and considered to be related to 
investigational product; cases of severe hypersensitivity that are determined 
to be related to investigational product; DILI that is related to 
investigational product; and pregnancy. SAEs related to investigational 
product are potential but not absolute reasons for dose discontinuation.
Sections 8.4, 8.4.1, and 8.4.2
Criteria for DILI have been added.
Section 8.4.2
Criteria for early termination of the study have been clarified.
Section 8.5
Clarification that original diary data should be entered into the eCRF and 
take precedence over data collected over the phone.
Section 9.1
Definition of PK analysis population has been added.
Section 9.6
Pharmacokinetic analyses methods and parameters have been clarified.
Synopsis
Section 9.10.1
Protocol history has been added in Appendix 1.
Appendix 1
Guidelines for nutritional support management during the study have been 
clarified.
Appendix 2
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APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY (SHP633-302)
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should be considered for managing nutritional support 
(PN/IV and EN [PN/EN]) in terms of volume and calories during the treatment period: 

Growth trajectory, including weight, height (or length), and head circumference (for children 
up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen/creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Form Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food and fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.
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APPENDIX 3
WEANING ALGORITHMS  
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in Diapers
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Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers
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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment
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CLINICAL TRIAL PROTOCOL: SHP633-302
TITLE:
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic 
Study of Teduglutide in Japanese Pediatric Subjects, Aged 4 Months 
through 15 Years, with Short Bowel Syndrome who are Dependent on 
Parenteral Support
NUMBER:
SHP633-302
PHASE:
3
DRUG:
Teduglutide 
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
 
PROTOCOL 
HISTORY:
Amendment 4: 12 Jun 2018
Amendment 3: 24 Jan 2018
Amendment 2: 06 Jun 2017
Amendment 1: 27 Apr 2016
Original Protocol: 18 Dec 2015
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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12 Jun 2018 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD PhD 
j 
 
__ 
___ _ _ ___ ___ ____ _ __ _ ________ 
_ _____________________________________________________ , 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-302. 
Title: A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 4 Months through 15 Years, 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 or subject's guardian in order to obtain their 
consent/assent 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 Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and 
Address: 
(please hand print or type) 
Signature: 
Date: 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 
Amendment 4
Amendment Date
12 Jun 2018
Global
Description of Change
Section(s) Affected by Change
Added enrollment of a minimum of 2 infants (4 to <12 months corrected 
gestational age) to the protocol due to medical need. 
Title Page; Protocol Signature Page, 
Study Synopsis, Section 2.2, 
Section 3.1, Section 4, Section 4.1
Changed Quintiles Transnational Japan K.K. to IQVIA Services Japan K.K 
to reflect a corporate name change.
Emergency Contact Information, 
Section 8.1.6, Section 8.2.2, 
Section 8.2.4, Section 8.2.7, 
Section 8.3
Clarified that planned enrollment is a minimum of 5 subjects aged 
1 through 15 years.
Study Synopsis, Section 4
Updated Inclusion Criterion #6 to define stable PN/IV for infants.
Study Synopsis, Section 4.1
Updated Exclusion Criterion #6 to clarify that the subject will be excluded 
if there is evidence of a clinically significant obstruction in the most recent 
upper gastrointestinal series done within 6 months prior to screening.
Study Synopsis, Table 1, Section 4.2, 
Section 7.2.14.1
Updated Exclusion Criterion #9 to specify that subjects with known cancer 
predisposition syndrome will also be excluded.
Study Synopsis, Section 4.2
Updated Exclusion Criteria #17 & 18 to remove references to 
hospitalizations in order not to exclude infants who are frequently 
chronically hospitalized.
Study Synopsis, Section 4.2
Updated Exclusion Criterion #19 to exclude subjects <5 kg.
Study Synopsis, Section 4.2
Added infant specific laboratory values to Exclusion Criterion #20. 
Removed the criteria for Gilbert’s disease as it was redundant.
Study Synopsis, Section 4.2
Specified that fecal occult blood testing was not required for infants.
Study Synopsis, Table 1, 
Section 7.2.4, Section 7.2.14.3
Specified that abdominal ultrasound was not required for infants.
Study Synopsis, Table 1, 
Section 7.2.4, Section 7.2.14.2
Specified that colonoscopy or sigmoidoscopy was not required for infants 
and that an upper endoscopy may be performed along with any colonoscopy 
at the discretion of the investigator.
Study Synopsis, Table 1, Table 2, 
Section 7.2.4, Section 7.2.14.4
Specified that PK samples may be reduced in smaller children for who 
blood sampling may impose an unacceptable phlebotomy volume.
Table 1, Section 7.2.5
Specified that results for infant subjects will be analyzed separately from 
those over 12 months of age.
Study Synopsis, Section 9.3
A planned interim analysis after completion of study participation of 
children 1-15 years of age has been added.
Section 9.4.1
Updated the details of the population PK analysis to be conducted.
Study Synopsis, Section 9.10.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 
Amendment 4
Amendment Date
12 Jun 2018
Global
Description of Change
Section(s) Affected by Change
Specified that safety labs at phone visits are at the discretion of the 
investigator for infants.
Table 1, Table 2, Section 7.2.8
Specified that plasma citrulline will not be collected from infants.
Table 1, Table 2, Section 7.2.4, 
Section 7.2.9
Added the contact information for the monitoring personnel. 
Appendix 4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout 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, the investigator must fax or e-mail the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to IQVIA Services Japan K.K. using the details below.
Pharmacovigilance SAE Reporting:
FAX: 
 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 between 8:00 to 20:00 US Eastern Standard Time, the 
investigator may contact the Shire medical monitor:
, MD, PhD, FAAP
Clinical Development Physician
Phone: 
Mobile: 
Email: 
In-country Clinical Caretaker:
 
: 
IQVIA Services Japan K.K.
Phone: 
Email:
Fax: 
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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 adverse events related to product complaints, see 
Section 8.
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
TABLE OF CONTENTS.................................................................................................................7
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULES..................................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................24
1.1
Indication and Current Treatment Options...............................................................24
1.2
Product Background and Clinical Information ........................................................24
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................27
2.1
Rationale for the Clinical Study...............................................................................27
2.2
Objective(s) ..............................................................................................................27
3
STUDY DESIGN ...................................................................................................................28
3.1
Study Design and Flow Chart ..................................................................................28
3.2
Study Duration .........................................................................................................29
3.3
Sites and Regions .....................................................................................................29
4
STUDY POPULATION.........................................................................................................30
4.1
Inclusion Criteria......................................................................................................30
4.2
Exclusion Criteria.....................................................................................................30
4.3
Reproductive Potential .............................................................................................34
4.4
Discontinuation of Subjects .....................................................................................34
4.4.1
Subject Withdrawal Criteria ..................................................................................34
4.4.2
Reasons for Discontinuation..................................................................................34
4.4.3
Subjects “Lost to follow-up” Prior to Last Scheduled Visit..................................35
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................36
5.1
Prior Treatment ........................................................................................................36
5.2
Concomitant Treatment............................................................................................36
5.3
Prohibited Treatment................................................................................................36
6
INVESTIGATIONAL PRODUCT ........................................................................................37
6.1
Identity of Investigational Product...........................................................................37
6.1.1
Blinding of the Treatment Assignment..................................................................37
6.1.2
Administration of Investigational Product.............................................................37
6.1.2.1
Administration by Parent/Guardian .......................................................38
6.1.3
Allocation of Subjects to Treatment ......................................................................39
6.2
Labeling, Packaging, and Storage............................................................................39
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6.2.1
Labeling and Packaging.........................................................................................39
6.2.2
Storage ...................................................................................................................39
6.3
Drug Accountability.................................................................................................39
6.4
Treatment Compliance .............................................................................................41
7
STUDY PROCEDURES........................................................................................................42
7.1
Study Schedule.........................................................................................................42
7.1.1
Screening................................................................................................................42
7.1.2
Treatment Period....................................................................................................42
7.1.3
Follow-up Period ...................................................................................................42
7.2
Study Evaluations and Procedures ...........................................................................43
7.2.1
Informed Consent...................................................................................................43
7.2.2
Study Entrance Criteria..........................................................................................43
7.2.3
Confirmation of Study Eligibility..........................................................................43
7.2.4
Demographics and Other Baseline Characteristics................................................43
7.2.5
Pharmacokinetic Assessments ...............................................................................44
7.2.6
Physical Examination (Including Height and Weight)..........................................45
7.2.7
Vital Signs..............................................................................................................45
7.2.8
Clinical Laboratory Tests.......................................................................................46
7.2.9
Plasma Citrulline....................................................................................................47
7.2.10 Antibody Assessments...........................................................................................47
7.2.11 Pregnancy Testing..................................................................................................47
7.2.12 Volume of Blood....................................................................................................47
7.2.13 Electrocardiogram..................................................................................................47
7.2.14 Gastrointestinal-specific Testing ...........................................................................48
7.2.14.1
Upper Gastrointestinal Series with Contrast ..........................................48
7.2.14.2
Abdominal Ultrasound ...........................................................................48
7.2.14.3
Fecal Occult Blood Testing....................................................................48
7.2.14.4
Colonoscopy/Sigmoidoscopy.................................................................49
7.2.15 Other Study Procedures .........................................................................................49
7.2.15.1
GI-specific Symptoms History...............................................................49
7.2.15.2
Nutritional Support.................................................................................49
7.2.15.3
Diaries ....................................................................................................50
8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ....................................51
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................51
8.1.1
Severity Categorization..........................................................................................51
8.1.2
Relationship Categorization...................................................................................52
8.1.3
Outcome Categorization ........................................................................................52
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8.1.4
Symptoms of the Disease Under Study .................................................................52
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................53
8.1.6
Pregnancy...............................................................................................................53
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................54
8.2
Serious Adverse Event Procedures ..........................................................................54
8.2.1
Reference Safety Information................................................................................54
8.2.2
Reporting Procedures.............................................................................................54
8.2.3
Serious Adverse Event Definition .........................................................................55
8.2.4
Serious Adverse Event Collection Time Frame.....................................................55
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................55
8.2.6
Fatal Outcome........................................................................................................56
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................56
8.3
Adverse Events of Special Interest...........................................................................56
8.4
Dose Interruption of Individual Subjects .................................................................57
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide.......................57
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury...........................59
8.5
Early Termination of the Clinical Study ..................................................................60
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................61
9.1
Data Collection.........................................................................................................61
9.2
Clinical Data Management.......................................................................................61
9.3
Statistical Analysis Process......................................................................................61
9.4
Planned Interim Analysis and Data Monitoring Committee....................................62
9.4.1
Planned Interim Analysis.......................................................................................62
9.4.2
Data Monitoring Committee..................................................................................62
9.5
Sample Size Calculation and Power Considerations................................................62
9.6
Study Population ......................................................................................................63
9.7
Demographics and Baseline Characteristics ............................................................63
9.8
Efficacy/Pharmacodynamic Analyses......................................................................63
9.9
Safety Analyses........................................................................................................64
9.10
Other Analyses .........................................................................................................65
9.10.1 Pharmacokinetic Analyses.....................................................................................65
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................66
10.1
Sponsor’s Responsibilities .......................................................................................66
10.1.1 Good Clinical Practice Compliance.......................................................................66
10.1.2 Public Posting of Study Information......................................................................66
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................66
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10.1.4 Study Suspension, Termination, and Completion..................................................66
10.2
Investigator’s Responsibilities .................................................................................67
10.2.1 Good Clinical Practice Compliance.......................................................................67
10.2.2 Protocol Adherence and Investigator Agreement..................................................67
10.2.3 Documentation and Retention of Records.............................................................67
10.2.3.1
Case Report Forms.................................................................................67
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................68
10.2.3.3
Financial Disclosure...............................................................................68
10.3
Ethical Considerations..............................................................................................68
10.3.1 Informed Consent...................................................................................................68
10.3.2 Institutional Review Board or Ethics Committee..................................................69
10.4
Privacy and Confidentiality......................................................................................70
10.5
Study Results/Publication Policy .............................................................................70
11 LIST OF REFERENCES........................................................................................................72
12 APPENDICES ........................................................................................................................73
Appendix 1
Protocol History .....................................................................................74
Appendix 2
Guidelines for Nutritional Support Management During the Study 
                  (SHP633-302).........................................................................................79
Appendix 3
Weaning Algorithms ..............................................................................80
Appendix 4
Monitoring Personnel.............................................................................82
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LIST OF IN-TEXT TABLES
Table 1
Study Schedule of Events – Screening to Week 12...................................19
Table 2 
Study Schedule of Events – Weeks 13 to 28 .............................................22
Table 3
Examples of Excluded Diseases and Illnesses...........................................33
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing.............44
Table 5
List of Laboratory Tests.............................................................................46
Table 6
Adverse Events that May Lead to Dose Interruption.................................58
LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram ..........................................................................................29
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUCss
AUC at steady state
BMI
body mass index
Cmax,ss
Cmax at steady state
Cmin,ss
minimum plasma concentration at steady state
CL/F
apparent clearance
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
eCRF
electronic case report form
EC
ethics committee
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IBD
inflammatory bowel disease
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ICH
International Conference on Harmonisation
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
NCI
National Cancer Institute
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
PN/EN
parenteral nutrition/ intravenous fluids and enteral nutrition
PN/IV
parenteral nutrition/intravenous fluids
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow-through
ULN
upper limit of normal
US
United States
Vλz/F
apparent volume of distribution
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STUDY SYNOPSIS
Protocol number: SHP633-302
Drug: Teduglutide
Study Title:
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of Teduglutide in Japanese Pediatric 
Subjects, Aged 4 Months through 15 Years, with Short Bowel Syndrome who are Dependent on Parenteral Support
Number of subjects: 
Planned enrollment is a minimum of 5 subjects aged 1 through 15 years and a minimum of 2 subjects of 4 to 
<12 months corrected gestational age.
Sites and Regions: Approximately 5 investigational sites in Japan are planned.
Study Duration:
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment. The end of study (EOS) 
visit will be scheduled at week 28, 4 weeks after the end of treatment (EOT) visit (week 24).
Investigational Product, Dose, and Mode of Administration: 
During the treatment period, a dose of 0.05 mg/kg/day of teduglutide will be administered once daily
subcutaneously (SC) to the subjects.
The dose calculation will be based on body weight measured at the baseline visit (visit 2) and may be adjusted at
week 12 (visit 14). No other adjustments to dose will be made during the study period, unless discussed with Shire 
medical monitor or designee.
The first dose of teduglutide will be administered by a study physician. The processes for training the 
parent/guardian to administer teduglutide and for providing oversight of study drug administration are described in 
the Site Training Guide.
Objective(s):
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and pharmacodynamics (PD), and 
pharmacokinetics (PK) of teduglutide in pediatric subjects (4 months through 15 years of age) with short bowel 
syndrome (SBS) who are dependent on parenteral support. 
Study Design:
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of teduglutide. The study 
population will include two cohorts: infants 4-<12 months corrected gestational age and children 1-15 years of age.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the requirements for 
nutritional support for each subject and to ensure adherence to eligibility parameters. Attempts should be made to 
limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the first 2 weeks (weeks 1 
and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, and 12). For the remainder of the treatment 
period, visits at the sites will be conducted every 3 weeks (at weeks 15, 18, 21, and 24). Scheduled telephone 
contacts will be made on all other weeks during the treatment period. At all site visits and during telephone contacts, 
safety will be monitored and nutritional support will be reviewed and adjusted as needed. The EOS visit will be 
scheduled at week 28, 4 weeks following EOT. Weekly telephone contact will be made during the interim weeks 
from EOT to EOS to monitor safety and any changes in nutritional support.
To maintain consistency across all centers, all attempts should be made to follow the nutritional support adjustment 
guidelines and weaning algorithms (developed with SBS expert input and to be provided in the protocol) for 
decisions regarding parenteral nutrition/intravenous fluids (PN/IV) support reduction and advances in enteral feeds 
based on weight gain, urine, and stool output in the setting of clinical stability. Any departure from the nutritional 
support adjustment guidelines and weaning algorithms will not constitute a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have positive/specific antibodies, 
they will be asked to return for a follow-up visit 3 months post EOT for another antibody sample. If the subjects 
continue to have positive/specific antibodies at 3 months post EOT, they will be asked to return for follow-up 
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visit(s) up to 6 months post-treatment in order to determine their antibody status.
Safety and tolerability results will be evaluated by a Data Monitoring Committee periodically during the active 
study period, based on subject enrollment.
All subjects who complete the study may participate in a long term extension study in which eligible subjects could 
receive teduglutide.
Study Inclusion and Exclusion Criteria:
Subjects who satisfy the following inclusion and exclusion criteria will be enrolled in the study.
Inclusion Criteria
1.
Informed consent by a parent or guardian prior to any study-related procedures
2.
When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the subject 
prior to any study-related procedures
3.
Male or female infant 4-<12 months corrected gestational age or child or adolescent aged 1 year through 15 
years
4.
Current history of SBS as a result of major intestinal resection (eg, due to necrotizing enterocolitis, midgut 
volvulus, intestinal atresia, or gastroschisis)
5.
Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or fluid/electrolyte 
needs
6.
Stable PN/IV support, defined as:
For infants 4 to <12 months corrected gestational age:
Inability to significantly reduce PN/IV support, usually associated with minimal or no advance in enteral 
feeds (ie, 10% or less change in PN or advance in feeds) for at least 1 month prior to and during screening, 
as assessed by the investigator.
For children 1 to 15 years of age:
Inability to significantly reduce PN/IV support, usually associated with minimal or no advance in enteral 
feeds (ie, 10% or less change in PN or advance in feeds) for at least 3 months prior to and during screening, 
as assessed by the investigator.
Transient instability for events such as interruption of central access or treatment of sepsis is allowed if the 
PN/IV support returns to within 10% of baseline prior to the event.
7.
Sexually active female subjects of childbearing potential must use medically acceptable methods of birth 
control during and for 4 weeks following the last dose of investigational product
Exclusion Criteria
1.
Subjects who are not expected to be able to advance oral or tube feeding regimens
2.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of 
screening
3.
Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and inability to 
reduce parenteral support
4.
Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial Adenomatous 
Polyposis, Fanconi-Bickel syndrome)
5.
Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active gastroschisis-
related dysmotility; that is the primary contributing factor to feeding intolerance and inability to reduce 
parenteral support, prior to screening. Dysmotility is defined as severe if it is expected to limit the advancement 
of enteral feeding.
6.
Evidence of clinically significant obstruction on the most recent upper gastrointestinal (GI) series done within 6 
months prior to screening
7.
Major GI surgical intervention including significant intestinal resection within 3 months prior to screening 
(insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections ≤10 cm, or endoscopic procedure 
is allowed)
8.
Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception of subjects who had 
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undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation 
9.
History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous basal or 
squamous cell carcinoma, or in situ nonaggressive and surgically resected cancer. Subjects with known cancer 
predisposition syndrome, such as juvenile polyposis or Beckwith-Wiedemann syndrome, or first degree relative 
with early onset of GI cancer (including hepatobiliary and pancreatic cancer) will also be excluded.
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 3 
months or 5.5 half-lives of the experimental drug, whichever is longer, prior to screening and for the duration of 
the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, antitumor necrosis factor 
[anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant therapy that 
had been introduced or changed during the 3 months prior to screening
17. More than 3 serious complications of SBS (eg, documented infection-related catheter sepsis, clots, bowel 
obstruction, severe water-electrolyte disturbances) within 3 months prior to the screening visit
18. A serious complication that affects parenteral support requirements within 1 month prior to or during screening, 
excluding uncomplicated treatment of bacteremia, central line replacement/repair, or issues of similar 
magnitude in an otherwise stable subject 
19. Body weight <5 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the screening period:
For infants 4 to <12 months corrected gestational age at least 2 of any of the following parameter:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
e. 
Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week period
For children 1 to 15 years of age:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results of an 
estimated glomerular filtration rate  below 50 mL/min/1.73 m2
22. Parent(s)/guardian(s) and/or subjects who are not capable of understanding or not willing to adhere to the study 
visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any undue 
risk, prevents completion of the study, or interferes with analysis of the study results. Examples of potential 
disease states/illnesses that may be excluded are listed in Table 3.
Pharmacokinetic Variables:
Blood samples for drug concentrations will be collected at the baseline visit (predose, at 1 and 6 hours postdose) and 
at week 4 visit (predose, 2 and 4 hours postdose). If blood samples are not/cannot be collected at week 4, the 
uncollected samples can be collected during any future site visit while the subject is still on investigational product. 
The following PK parameters will be derived using a population PK modeling approach and reported separately:

Area under the concentration-time curve at steady-state (AUCtau,ss)
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
Maximum plasma concentration at steady-state (Cmax,ss)

Minimum plasma concentration at steady-state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Efficacy/Pharmacodynamic Assessments:
The efficacy/PD endpoints include:

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), citrulline, and 
enteral nutritional support (volume and calories), separately, at each visit

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) compared to 
baseline

≥20% reduction in PN/IV volume at each visit

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support
Safety Assessments:
Safety and tolerability will be assessed by evaluating the following:

Adverse events, including those pertaining to GI symptoms.

Physical examinations, including body weight, height (or length), head circumference (up to 36 months of age), 
and trends on growth charts

Vital signs, including temperature, heart rate, blood pressure

Electrocardiograms (ECGs)

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

For children 1 to 15 years of age: GI-specific testing including colonoscopy or sigmoidoscopy, abdominal 
ultrasound, fecal occult blood testing, upper GI series with small bowel follow-through (UGI/SBFT). 
For infants 4 to <12 months corrected gestational age: UGI/SBFT.
Safety and tolerability will be evaluated by a Data Monitoring Committee during the study period.
Statistical Methods:
Due to the limited size of the study population, descriptive statistics will be used with a goal of summarizing the 
sample. As such, no claims of significance will be made for any of the data.
Pharmacokinetic parameters will be estimated based on measured teduglutide plasma concentrations using a 
population PK modeling approach and reported separately.
Continuous variables will be summarized using descriptive statistics including number of subjects, mean, median, 
standard deviation, maximum, and minimum. For categorical variables, statistical summaries will include number of 
subjects and percentages.
Efficacy/PD data will include change in PN/IV support, enteral nutritional support, plasma citrulline, and hours per 
day and days per week of PN/IV support, and will be summarized by visit.
Safety data will include clinical laboratory tests results; measurement of body weight, height (or length), and head 
circumferences (if applicable); vital signs; concomitant medications; and ECG monitoring; and will be summarized
by visit. Adverse events will also be collected and summarized. Descriptive statistics will be calculated for 
quantitative safety data as well as for the difference from baseline, if applicable. Frequency counts will be compiled 
for classification of qualitative safety data.
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Data will be analyzed and presented by subject cohorts. The infant cohort will be analyzed in a manner analogous to 
the pediatric cohort unless specified otherwise.
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STUDY SCHEDULES
Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Informed 
consent/assenta
X
Eligibility
X
X
Demographics 
X
Medical /surgical 
history
X
Electrocardiogram
X
X
SBS history
X
Upper GI with small 
bowel follow-through 
and abdominal 
ultrasoundb
X
Fecal occult blood 
testingc
X
X
Colonoscopy/ 
sigmoidoscopyc
(X)
(X)
Provide GI-specific 
symptoms history diary
X
Review GI-specific 
symptoms history diary
X
Dispense 
investigational productd
X
X
X
X
X
X
X
X
Confirm administration 
proficiency
Xn
Xn
Xn
X
X
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
Pharmacokinetic 
sampling
Xe
Xf
Safety laboratory testsg
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testingh
X
X
X
X
X
X
X
X
X
Plasma citrullinei
X
X
Antibodies to 
teduglutidej
X
Provide intake and 
output diaries
X
X
X
X
X
X
X
X
X
Review diaries and 
nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Physical examination/ 
vital signs/weight
X
X
X
X
X
X
X
X
X
Height (or length) and 
head circumferencem
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; eCRF=electronic case report form; EN=enteral nutrition; FOBT=fecal occult blood testing; GI=gastrointestinal; PK=pharmacokinetic; PT/INR=prothrombin 
time/international normalized ratio; PN/IV=parenteral nutrition/intravenous fluids; SBS=short bowel syndrome; SC=subcutaneous; UGI/SBFT= upper GI series with small 
bowel follow through
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Table 1
Study Schedule of Events – Screening to Week 12
Procedures
Screen-
ing
Baseline
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 9
Week 
10
Week 
11
Week 
12
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study day
±window (days)
≥-14
0
7
2
14
2
21
3
28
3
35
3
42
3
49
3
56
3
63
3
70
3
77
3
84
3
a
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b
If the subject has undergone an UGI/SBFT and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable for the screening assessments. 
However, if the most recent UGI/SBFT prior to screening shows evidence of obstruction, the UGI/SBFT should be repeated during screening. The procedure(s) are to be performed any time after 
providing informed consent with the results available and reviewed before the baseline visit (day 0). Abdominal ultrasound will not be performed for infant subjects.
c
Fecal occult blood test (FOBT) and colonoscopy are not to be performed for infant subjects. Subjects over 12 months of age will have FOBT after providing consent/assent. Those with positive 
FOBT at screening for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or sigmoidoscopy. Colonoscopy or sigmoidoscopy will be conducted at 
screening on all subjects 12 years of age and older; however if the screening FOBT is negative and the subject has undergone the procedure within 1 year before visit 1 (screening), then that result 
will be acceptable for the screening assessment (Section 7.2.14.4). Positive FOBT results at week 12 should be discussed with the medical monitor. Upper endoscopy may be performed along with 
any colonoscopy at the discretion of the investigator (Section 7.2.14.3).
d
The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at least 4 hours. The site of 
administration (arm, thigh, abdomen) must be specified and recorded in the eCRF. The dose of study medication may be adjusted at week 12.
e
Baseline (visit 2) samples for PK analysis will be drawn predose, and 1 hour ± 10 minutes and 6 hours ± 30 minutes postdose (Section 7.2.5).
f
Week 4 (visit 6) samples for PK analysis will be drawn predose, and 2 hours± 10 minutes and 4 hours± 30 minutes postdose (Section 7.2.5). If blood samples are not/cannot be collected at Week 
4, the uncollected samples can be collected during any future site visit while the subject is still on investigational product. In smaller children for whom blood sampling may impose unacceptable 
phlebotomy volume, the number of PK samples may be reduced. 
g
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits (eg, biochemistry and 
urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation. For children over 12 months of age, safety labs must be performed approximately 5 to 7 days following any adjustment to the PN/IV prescription. 
For infants, safety labs at phone visits are at the discretion of the investigatory. PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy: serum testing at screening; urine testing thereafter. 
i
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access (Section 7.2.9). Plasma 
citrulline will not be collected from infant subjects.
j
Blood sample for antibody testing is to be collected at study site prior to first investigational product administration. Blood samples may be drawn from a central line or peripheral access 
(Section 7.2.10).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study by the subject or parent/guardian/study site staff 
(Section 7.2.15.3). Urine and stool output should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV 
prescription. (Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support management and weaning 
algorithms provided in Appendix 2 and Appendix 3, respectively.
m
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
n
The first dose of teduglutide will be administered by a study physician. The study physician must observe the parent/guardian administer the study drug in compliance with the study drug 
administration checklist at least twice before the parent/guardian is allowed to administer the drug without direct observation by the physician. Refer to Section 6.1.2.1.
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit.
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week 
13
Week 14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(or 
EOT/ET)a
Weeks 25, 
26, 27
Week 28
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day 
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Dispense 
investigational product
X
X
X
Provide intake and 
output diaries
X
X
X
X
Review diaries and 
nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional 
supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testsd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Pregnancy testinge
X
X
X
X
X
Plasma citrullinef
X
X
Antibodies to 
teduglutideg
X
X
Physical examination/
vital signs/weight
X
X
X
X
X
Height (or length) and 
head circumferenceh
X
X
X
X
X
Fecal occult blood 
testingi
X
Colonoscopy/ 
sigmoidoscopyi
(X)
Electrocardiogram
X
X
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Table 2
Study Schedule of Events – Weeks 13 to 28
Procedures
Week 
13
Week 14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(or 
EOT/ET)a
Weeks 25, 
26, 27
Week 28
(or EOS)
Visit number
15
16
17
18
19
20
21
22
23
24
25
26
27-29
30
Visit type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Site
Study day 
±window (days)
91
3
98
3
105
3
112
3
119
3
126
3
133
3
140
3
147
3
154
3
161
3
168
3
175, 182, 
189
3
196
4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication/
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PN/IV=parenteral nutrition/intravenous fluid
a
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 7.2.15.3). Urine and stool output 
should be recorded in the output diary over a 48 hour period of PN/IV and EN stability before every site visit and within 1 week of each change in PN/IV prescription. 
(Section 7.2.15.3 for more details). Nutritional support includes PN/IV and EN (formula) (Section 7.2.15.2).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support 
management and weaning algorithms provided in Appendix 2 and Appendix 3, respectively.
d
Safety lab assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits 
(eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at the investigational site. For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation. For children over 12 months of age, safety labs must be performed 
approximately 5 to 7 days following any adjustment to the PN/IV prescription. For infants, safety labs at phone visits are at the discretion of the investigator. PT/INR will be 
tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy (urine testing). 
f
Blood samples for measuring citrulline levels will be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access 
(Section 7.2.9). Plasma citrulline will not be collected from infant subjects. 
g
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, at least 14 hours after the previous dose of teduglutide. If a blood sample is positive for 
antibodies at week 28 or EOS, then the subject will be retested 3 months after EOT. If that sample is positive, then the subject will be retested 6 months after EOT. 
h
Head circumference will be measured in subjects 36 months of age and younger (Section 7.2.6). 
i
Fecal occult blood test (FOBT) and colonoscopy are not to be performed for infant subjects enrolled. Subjects over 12 months of age with positive FOBT at week 24 
(EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory colonoscopy or sigmoidoscopy. Upper endoscopy may be 
performed along with any colonoscopy at the discretion of the investigator (Section 7.2.14.3).
Note: A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an unscheduled visit
Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate the subject visits to the site.
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease which results in major surgical resections of the small intestine. In children, 
most cases of SBS begin in infancy. Common causes of SBS in children include necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. (Duro et al., 2008; Squires et 
al., 2012) Similar to adults, new-onset SBS in older children usually stems from Crohn’s disease, 
trauma, and cancer. The diminished absorptive capacity for fluids and nutrients often results in 
dependence on parenteral nutrition or intravenous fluids (PN/IV) to maintain energy and fluid 
and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus height 
and crypt depth, dilation, and delayed intestinal transit. The main principle of management of 
SBS is to provide the minimal necessary parenteral support to maintain energy, fluid, and 
electrolyte homeostasis while maximizing enteral feeding to promote intestinal adaptation. In 
infants, rapid linear growth of the intestines during the first year of life dramatically 
complements the aforementioned adaptive responses. About 30% of infants who develop SBS 
during the neonatal period become independent of PN/IV requirements by 12 months of age, and 
an additional 10% wean off PN/IV support by 24 months of age. After this time, linear intestinal 
growth slows. About 60% of children with SBS are able to become independent of parenteral 
support within 5 years. (Khan et al., 2015; Squires et al., 2012) Nevertheless, despite optimal 
medical management, many children remain dependent on PN/IV support.
Complications of long-term parenteral support include liver disease, catheter-related blood 
stream infections, central line-associated venous thrombosis and dwindling central venous 
access. Sepsis is the leading cause of death in these patients, and quality of life is poor. 
Accelerating the adaptive process is an urgent goal for all patients with SBS who are dependent 
on parenteral support.
For this reason, research in the pediatric arena is focused on children with PN/IV-dependent 
SBS. Given intestinal adaption in younger children, the unmet medical need is the greatest in 
children who are 1 year of age and older. It is highly unlikely that children with less than 10% of 
the expected length of small intestine reach enteral independence. These subjects reach a plateau 
in their ability to advance oral/enteral feeds or decrease PN/IV support (ie, are “stuck”) and are 
not expected to achieve spontaneous adaptation. Subjects who have not progressed to full enteral 
adaptation by 12 months after their intestinal insults are very unlikely to demonstrate 
spontaneous improvement in their enteral function. (Sigalet et al., 2011)
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide-2 (GLP-2), which is secreted from L-type 
enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
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There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS. In the US and Europe, a GLP-2 analog called teduglutide is approved for the treatment 
of SBS in adult patients who are dependent on PN/IV support.
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 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. (Thymann et al., 2014; Tappenden et al., 
2013)
Clinical Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries. Two 
completed adult studies (CL0600-004 and its extension, CL0600-005) evaluated safety and 
tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were dependent 
on parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, 
placebo-controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, 
assessed the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was 
a statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study. At week 24, the weekly reduction of PN/IV 
volume was similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, 
assessed the long-term safety of teduglutide and the proportion of responders in the CL0600-004 
study that maintained their response at the end of a further 28 weeks of treatment. The extension 
study also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in 
PN/IV. Seventy-five percent of the subjects who previously responded to teduglutide treatment 
in Study CL0600-004 maintained this response or experienced further improved benefit from 
teduglutide treatment. More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. Most of the adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
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12 Jun 2018
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus 
13/43 subjects [30.2%], respectively). 
This difference was clinically and statistically significant in both the intent-to-treat (ITT) 
(p=0.002) and per-protocol (p < 0.001) populations. Generally, the incidence of treatment-
emergent AEs was distributed similarly across all treatment groups. The treatment-emergent AEs 
with a higher incidence in the teduglutide group were mainly of GI origin. A long-term, 
open-label extension study (CL0600-021) assessed safety and efficacy for up to 24 additional 
months (ie, up to 30 months of exposure for subjects who received teduglutide in Study CL0600-
020). Overall, 30 of 43 subjects who received teduglutide in Study CL0600-020 and entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide. Of these, 
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a PN/IV 
volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative to 
baseline prior to exposure to teduglutide at the beginning of Study CL0600-020. PN/IV use was 
reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 30 months of 
treatment. Of the 39 subjects who entered Study CL0600-021 after receiving placebo in 
Study CL0600-020, 29 completed 24 months of treatment with teduglutide. The mean reduction 
in PN/IV volume was 3.11 L/week from baseline at the start of Study CL0600-021 (a 28% 
reduction). Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction of 
parenteral support. Of the 12 subjects entering Study CL0600-021 directly, 6 completed 
24 months of treatment with teduglutide. The mean reduction in PN/IV volume was 4.0 L/week 
(a 39.4% reduction from baseline at the start of Study CL0600-021) and 4 of the 6 completers 
(66.7%) achieved a 20% or greater reduction of parenteral support.
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU countries. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts. 
There were no deaths during the study and no treatment-emergent AEs related to teduglutide 
were reported. No discontinuations from study were due to AEs.
Additional information is provided in the investigator’s brochure.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Clinical Study 
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014. 
Based on national surveys, it is estimated that the number of subjects with SBS who are 
dependent on parenteral nutrition/intravenous fluid (PN/IV) is less than 1000 in Japan. (Takagi et 
al., 1995; Takehara, 2001; Kitajima et al., 2013) Among the 195 SBS subjects in the 2011 
survey, 99 (51%) developed SBS at <1 years old. Early intervention could potentially improve 
intestinal adaptation and decrease the need for parenteral support in these patients.
The current study proposes to investigate the safe and appropriate use of teduglutide in the 
Japanese pediatric population for the purpose of providing pharmacokinetic (PK), 
pharmacodynamic (PD), and safety data. This protocol was developed similarly to the planned 
EU/US study, TED-C14-006, A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic 
Study Investigating Two Doses of Teduglutide in Pediatric Subjects through 17 Years of Age, 
with Short Bowel Syndrome who are Dependent on Parenteral Support. The TED-C14-006 
protocol was developed with input from expert advisors from intestinal rehabilitation centers 
who offered advice on the most appropriate use of teduglutide in pediatric patients. The 
teduglutide dose of 0.05 mg/kg daily is supported by results from the completed 12-week 
pediatric study. Teduglutide is approved for adult use in the US and EU at a dose of 0.05 mg/kg 
SC once daily. The completed 12-week pediatric study (TED-C13-003, A 12-Week 
Pharmacokinetic, Safety, and Pharmacodynamic Study of Teduglutide in Pediatric Subjects 
Aged 1 Year through 17 Years, with Short Bowel Syndrome who are Dependent on Parenteral 
Support) demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with 
a favorable benefit/risk profile. In addition, population PK modeling and simulations were 
conducted to determine the effective dose to be used in pediatric subjects using data from 8 adult 
clinical studies including adult Phases 1, 2, and 3 studies as well as the pediatric study (TED-
C13-003); they suggested that the dose in pediatric subjects is likely to be the same as the dose in 
adults. (O'Keefe et al., 2006) The duration of teduglutide treatment in study SHP633-302 mirrors 
that of the TED-C14-006 study, consisting of 24 weeks of teduglutide treatment, followed by a 
4-week follow-up period.
The aim of teduglutide treatment is to increase absorptive capacity in order to yield decreases in 
parenteral support. In addition, the experts anticipated that there would be several direct benefits 
from decreased parenteral support and advances in enteral feeds, including less exposure to 
PN/IV constituents, less central line manipulation with lower risk of infection, and more time to 
focus on oral rehabilitation strategies.
2.2
Objective(s) 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and PD, and PK 
of teduglutide in pediatric subjects (4 months through 15 years of age) with SBS who are 
dependent on parenteral support. See Sections 9.8 and 9.10.1 for further details of the endpoints 
being measured, and Section 9.9 for safety variables.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of 
teduglutide. The study population will include 2 cohorts: infants 4-<12 months corrected 
gestational age and children 1-15 years of age.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. Attempts should be made to limit the screening period to 4 weeks.
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks (weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 10, 
and 12). For the remainder of the treatment period, visits at the sites will be conducted every 
3 weeks (at weeks 15, 18, 21, and 24). Scheduled telephone contacts will be made on all other 
weeks during the treatment period. At all site visits and during telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed. The end of study 
(EOS) visit will be scheduled at week 28, 4 weeks following end of treatment (EOT). Weekly 
telephone contact will be made during the interim weeks from EOT to EOS to monitor safety and 
any changes in nutritional support. The Study Schedules (Table 1 and Table 2) are displayed at 
the beginning of this protocol.
A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as 
an unscheduled visit.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines and weaning algorithms (developed with SBS expert input and 
provided in Appendix 2 and Appendix 3, respectively) for decisions regarding PN/IV support 
reduction and advances in enteral feeds based on weight gain, urine, and stool output in the 
setting of clinical stability. Any departure from the nutritional support adjustment guidelines and 
weaning algorithms will not constitute a protocol deviation.
At the conclusion of the follow-up period (week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post EOT 
for another antibody sample. If the subjects continue to have positive/specific antibodies at 
3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) which 
will convene approximately every 3 months during the active study period, based on subject 
enrollment.
All subjects who complete the study may participate in a long term extension study in which 
eligible subjects could receive teduglutide.
A schematic representation of the study design is displayed in Figure 1.
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Figure 1
Study Diagram
EOS=end of study; EOT=end of treatment 
3.2
Study Duration
There will be, at a minimum, a 2-week screening period from the time of the screening visit to 
the baseline visit, followed by 24 weeks of treatment. Attempts should be made to limit the 
screening period to 4 weeks. The EOS visit will be scheduled at week 28, 4 weeks after the EOT 
visit (week 24). 
The start of the clinical phase is defined as first subject consented. The end of the clinical phase 
is defined as the last visit of the last subject.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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STUDY POPULATION 
Planned enrollment is a minimum of 5 subjects aged 1 through 15 years and a minimum of 
2 subjects of 4 to <12 months corrected gestational age.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Informed consent by a parent or guardian prior to any study-related procedures
2. When applicable, informed assent (as deemed appropriate by the Institutional Review Board) 
by the subject prior to any study-related procedures 
3. Male or female infant 4 to <12 months corrected gestational age or child or adolescent aged 
1 year through 15 years
4. Current history of SBS as a result of major intestinal resection (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
5. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs
6. Stable PN/IV support, defined as:
For infants 4 to <12 months corrected gestational age:
Inability to significantly reduce PN/IV support, usually associated with minimal or no 
advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at least 
1 month prior to and during screening, as assessed by the investigator. 
For children 1 to 15 years of age:
Inability to significantly reduce PN/IV support, usually associated with minimal or no 
advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at least 3 
months prior to and during screening, as assessed by the investigator.
Transient instability for events such as interruption of central access or treatment of sepsis is 
allowed if the PN/IV support returns to within 10% of baseline prior to the event.
7. Sexually active female subjects of childbearing potential must use medically acceptable 
methods of birth control during and for 4 weeks following the last dose of investigational 
product.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects who are not expected to be able to advance oral or tube feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support
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4. Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility; that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on the most recent upper GI series done within 
6 months prior to screening.
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ nonaggressive and surgically resected 
cancer. Subjects with known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of GI cancer 
(including hepatobiliary and pancreatic cancer) will also be excluded.
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic GLP-2
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 serious complications of SBS (eg, documented infection-related catheter sepsis, 
clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the 
screening visit
18. A serious complication that affects parenteral support requirements within 1 month prior to 
or during screening, excluding uncomplicated treatment of bacteremia, central line 
replacement/repair, or issues of similar magnitude in an otherwise stable subject
19. Body weight <5 kg at screening and baseline visits
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20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period:
For infants 4 to <12 months corrected gestational age at least 2 of any of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
e. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period
For children 1 to 15 years of age:
a.
Total bilirubin ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate below 50 mL/min/1.73 m2
22. Parent(s)/guardian(s) and/or subjects who are not capable of understanding or not willing to 
adhere to the study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results. Examples of potential disease states/illnesses that may be excluded are listed in 
Table 3. 
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Table 3
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in the GI tract 
identified by upper GI series, biopsy or polypectomy 

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis 

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug abuse within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease
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4.3
Reproductive Potential 
Sexually active females of childbearing potential must be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 4 weeks following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception if they become sexually active during the 
period of the study and 4 weeks following the last dose of investigational product.
Female children and adolescent subjects should be either:
Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or
Females of childbearing potential with a negative serum β-HCG pregnancy test at the screening 
visit (visit 1) and a negative urine β-HCG pregnancy test prior to enrollment. Females of 
childbearing potential must agree to abstain from sexual activity (ie, true abstinence) that could 
result in pregnancy or agree to use medically acceptable methods of contraception at all times 
during the study and 4 weeks following the last dose of investigational product.
Note: True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).
4.4
Discontinuation of Subjects
4.4.1
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to further treatment. However, a discussion should be 
held by the investigator and the Shire medical monitor or designee prior to the subject 
discontinuing or withdrawing. 
4.4.2
Reasons for Discontinuation

Reasons for discontinuation may include but are not limited to:

Adverse event

Death

Failure to meet enrollment criteria

Lost to follow-up

Non-compliance with investigational product

Physician decision

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Technical problems

Withdrawal by parent/guardian

Withdrawal by subject
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In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 8.1. 
To the extent possible, all examinations scheduled for the EOT evaluation must be performed on 
all subjects who participate even if they do not complete the study according to the protocol 
(ie, early termination). Any subject who discontinues treatment prematurely will be asked to 
return 4 weeks later for the EOS visit and will be contacted weekly for wellness checks during 
the interim period between EOT and EOS.
4.4.3
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 timepoint prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including non-prescription herbal treatments, vitamins, invasive and 
diagnostic procedures) received within 14 days prior to the screening visit (visit 1) and through 
the end of study (ie, including the protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 14 days of the first dose of investigational 
product, but discontinued before the first dose of investigational product. 
5.2
Concomitant Treatment
Concomitant medications are those that continue after the start of investigational product or are 
newly introduced after the start of treatment through the end of study. In all instances the start 
date of prior and concomitant therapies must be recorded to the extent possible.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
Changes in any medication and/or dosage will be recorded on the eCRF. See also nutritional 
support in Section 7.2.15.2.
5.3
Prohibited Treatment
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The following prior therapies are excluded within the timeframes noted (see Section 4.2).
Prior Therapy
Time Restriction Prior 
to Screening
Native/synthetic glucagon-like peptide-2
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy used to treat inflammatory bowel disease (eg, antitumor 
necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Teduglutide for subcutaneous (SC) injection is provided in 3 mL vials containing 5 mg or 
1.25 mg teduglutide as a lyophilized powder that must be reconstituted using 0.5 mL of sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the investigator’s brochure.
6.1.1
Blinding of the Treatment Assignment
Not applicable.
6.1.2
Administration of Investigational Product
A dose of 0.05 mg/kg/day of teduglutide will be administered once daily to the subjects for 
24 weeks. The dose calculation will be based on body weight measured at the baseline visit 
(visit 2) and may be adjusted at week 12 (visit 14). No other adjustments to dose will be made 
during the study period, unless discussed with the Shire medical monitor or designee.
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Each day, the injection site should be rotated. The site of administration (arm, thigh, abdomen) 
of the first teduglutide dose must be specified and recorded in the eCRF.
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later. Detailed instructions for reconstitution and injection of the investigational product can be 
found in the Instructions for Use.
The subject should be dosed at approximately the same time each day. If a dose is delayed, that 
day’s dose should be administered as soon as possible, but consecutive doses should be separated 
by at least 12 hours.
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6.1.2.1
Administration by Parent/Guardian
The first dose of teduglutide will be administered by a study physician and the subject is 
observed for possible hypersensitivity reactions for at least 4 hours during their initial dosing 
visit. 
The processes for training the parent/guardian to administer teduglutide and for providing 
oversight of study drug administration are described in the Site Training Guide. Before a 
parent/guardian is permitted to administer teduglutide, the study physician must observe the 
parent/guardian administering the study drug at least twice in compliance with the teduglutide 
administration checklist. The checklist is included as an Appendix to the Site Training Guide. 
After the study physician certifies that the parent/guardian can safely administer the study drug, 
subsequent doses may be administered by the parent/guardian at home without direct supervision 
by the physician. However, at selected study visits during the dosing period (refer to Table 1), 
administration of the study drug must be performed under direct supervision by the study 
physician, and the teduglutide administration checklist must be completed again. This ensures 
that the parent/guardian continues to administer the study drug correctly and safely throughout 
the dosing period.
If at any time a study physician suspects that the parent/guardian is no longer capable of 
administering the study drug safely and accurately, the parent/guardian should be reassessed by a 
study physician using the teduglutide administration checklist. If the parent/guardian is deemed 
unable to administer the study drug, dosing must be performed by a study physician until the 
parent/guardian is retrained and proficiency is confirmed using the teduglutide administration 
checklist. 
Eligibility for teduglutide to be administered by a parent/guardian will be judged by a study 
physician using the following criteria. Refer to the checklist included as an appendix to the Site 
Training Guide.
Criteria to Initiate Teduglutide Administration by the Parent/Guardian:

The subject’s condition is stable.

The parent/guardian has been sufficiently trained and is able to administer teduglutide 
in compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Parent/Guardian:

The parent/guardian is unable to administer teduglutide in compliance with the 
checklist.

The subject’s condition has deteriorated such that the study physician assesses it is 
inappropriate for the subject to have teduglutide administered by their 
parent/guardian. In addition to discontinuing administration of teduglutide by the 
parent/guardian, if a subject sustains an adverse drug reaction where the symptoms 
are considered intolerable, dose interruption or study drug discontinuation should be 
considered (see Section 8.4). 
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
In the study physician’s judgment, it is inappropriate for the parent/guardian to
continue administration of the study drug for any other reason.
6.1.3
Allocation of Subjects to Treatment 
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day as described in 
Section 6.1.2. Subject numbers are assigned to all subjects as consent/assent to take part in the 
study is provided. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. These 
numbers will be used to identify the subjects throughout the study period. Once a number/unique 
identifier has been assigned, that number must not be used again if, for example, a subject is 
withdrawn from the study. If a unique identifier is allocated incorrectly, the study monitor must 
be notified as soon as the error is discovered.
6.2
Labeling, Packaging, and Storage
6.2.1
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 Practices.
6.2.2
Storage
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 and 8oC 
until dispensed to a subject. The pre-filled sterile water for injection syringes will be stored at a 
temperature between 2 and 25°C. Once dispensed/supplied to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25oC). Parent/guardian will be instructed to keep the subject’s investigational product and sterile 
water diluent at controlled room temperature. If there are concerns that the controlled room 
temperature cannot be maintained, the investigational product may be refrigerated.
6.3
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the study visits at which the subject is required to be at 
the clinic. Each investigational product kit is sufficient for a treatment period of 1 week and 
enough kits will be supplied to cover the period until the next planned study visit. Additional 
study kits will be provided as necessary.
Each subject will be given the investigational product according to his/her treatment assignment. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. All dispensed medication will be documented on the eCRFs and/or other 
investigational product record. The investigator is responsible for assuring the retrieval of all 
study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
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.
See the Pharmacy Manual for additional information.
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6.4
Treatment Compliance
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by reviewing the subject diaries and asking the subject, 
the subject’s parent or guardian, or the study site staff if they have administered the 
investigational product according to instructions. If any doses have been missed, the reason for 
missed dose should be documented in the subject’s source documentation including, as 
applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc. 
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. Subjects falling outside of these parameters will not be included in the per-protocol 
efficacy analyses (see Section 9.6).
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7
STUDY PROCEDURES
7.1
Study Schedule
Subject evaluations will be performed during the indicated days and weeks of the study as 
provided in the Study Schedules (Table 1 and Table 2). 
All data collected are to be recorded on the appropriate eCRF.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1.1
Screening
All subjects’ parents/guardians must sign an informed consent form and, if applicable, subjects 
must sign an informed assent form prior to initiation of any study-related procedure. All subjects 
will be screened for a minimum of 2 weeks. Attempts should be made to limit the screening 
period to 4 weeks.
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigation product.
At the discretion of the investigator, subjects who fail screening may be rescreened one time with 
prior sponsor approval. In the event of rescreening, a new subject number will be assigned to the 
subject and the subject will also be reconsented.
7.1.2
Treatment Period
Subjects who meet all eligibility criteria at screening, and eligibility criteria are confirmed at 
visit 2/baseline, will be enrolled in the study and will receive the first dose of investigational 
product at the baseline visit (visit 2). Subjects will enter a 24-week treatment period consisting of 
either visits or scheduled weekly telephone contacts as outlined in the Section 3.1.
7.1.3
Follow-up Period
During the 4-week follow-up period, weekly telephone visits will be conducted on week 25 to 
week 27 followed by the EOS visit (week 28). Similar to assessments performed during the 
treatment period, phone visits during follow-up will include review of intake diaries, and 
adjustment of nutritional support as needed (see Section 3.1). Procedures to be performed at the 
EOS visit (week 28) are specified in the Study Schedules (Table 1 and Table 2); subjects will be 
queried on serious adverse events (SAEs), AEs, and concomitant treatments, and all AEs and 
SAEs that are not resolved at the time of this visit will be followed to closure (see Section 8.1).
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7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (and, when 
applicable, informed assent) must be obtained from the subject’s parent(s) or guardian(s) and 
from the subject (if applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s guardian(s) by the investigator or 
designee in accordance with the guidelines described in Section 10.3.1. Documentation and 
filing of informed consent documents should be completed according to Section 10.2.
7.2.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria by 
the investigator or designee. Subjects who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the subject’s ineligibility for the study will 
be documented.
7.2.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at 
baseline by the investigator or designee on the basis of review of the study entrance criteria.
7.2.4
Demographics and Other Baseline Characteristics
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy

GI-specific symptoms history (Section 7.2.15.1)

Physical examination, including body weight, height (or length), and head circumference (up 
to 36 months of age), and trends on growth charts

Vital signs including temperature, heart rate, and blood pressure

Prior medications (medications used within 14 days prior to screening and discontinued prior 
to the first dose of investigational product), including drug name, dose, route, reason for use, 
and therapy dates. Medications used during the treatment period (after the first dose of 
investigational product) will be recorded as concomitant medications.

Electrocardiogram (ECG) (12-lead) variables include general findings (normal/ abnormal, 
not clinically significant/ abnormal, clinically significant). The cause of any clinically 
significant ECG will be specified.
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
Laboratory test results: biochemistry, hematology, coagulation, and urinalysis

Plasma citrulline levels will be obtained in subjects over 12 months of age

Presence of antibodies to teduglutide and titer level, if present

Gastrointestinal imaging/testing (Section 7.2.14)
For children 1 to 15 years of age: GI-specific testing including colonoscopy or 
sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, upper GI series with 
small bowel follow-through.
For infants 4 to <12 months corrected gestational age: upper GI series with small bowel 
follow-through.

Pregnancy testing for females of childbearing potential

Nutritional support prescriptions (eg, PN/IV and enteral nutrition [EN] volume and calories, 
PN/IV hours per day and days per week) (Section 7.2.15.2)

Nutritional support diary data (Section 7.2.15.3)
7.2.5
Pharmacokinetic Assessments
Pharmacokinetic assessments are listed in Section 9.10.1. 
Blood samples for teduglutide concentrations will be collected at the baseline and week 4 visits. 
If blood samples are not/cannot be collected at Week 4, the uncollected samples can be collected 
during any future site visit while the subject is still on investigational product. In smaller children 
for whom blood sampling may impose unacceptable phlebotomy volume, the number of PK 
samples may be reduced. A schedule of PK sample collection is provided in Table 4. Instructions 
for sample collection and handling are included in the Laboratory Manual.
Table 4
Blood Sample Collection Schedule for Pharmacokinetic Testing
Study week
Baseline
Week 4
Visit Number
2
6
Hour
0a
1
6
0a
2
4
a Prior to investigational product administration
The timepoints indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these timepoints may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

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 (at the week 4 draw).

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes

6-hour postdose draw: ±30 minutes
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At PK timepoints, the date and time of investigational product administration and blood 
collection must be recorded on the eCRF.
7.2.6
Physical Examination (Including Height and Weight)
Physical examinations will be performed, and body weight, height (or length), and head 
circumference (up to 36 months of age) measured according to the Study Schedules (Table 1 and 
Table 2).
Physical examinations will be performed by the investigator during the study 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.
Subjects should be weighed on the same scale at each study visit. Height (or length [cm]) and 
head circumference (for subjects ≤36 months of age[cm]) will be measured at selected visits.
Body mass index (BMI) and z-scores for weight, height (or length), head circumference, and 
BMI will be calculated by the sponsor.
7.2.7
Vital Signs
Vital signs will be measured according to the Study Schedules (Table 1 and Table 2). 
Measurements will include body temperature (°C), heart rate (beats per minute), and systolic and 
diastolic blood pressure (mmHg). Blood pressure should be determined by cuff (using the same 
method, the same extremity, 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.
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7.2.8
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing according to the Study Schedules (Table 1 and Table 2). Subjects should be in a seated or 
supine position during blood collection.
Laboratory collections required at intervals that do not coincide with site visits (safety laboratory 
assessments eg, biochemistry and urinalysis following PN/IV adjustments) will be performed at 
the investigational site. For infants, safety labs at phone visits are at the discretion of the 
investigator.
Clinical laboratory tests will include the following (see Table 5):
Table 5
List of Laboratory Tests
Hematology:
Hematocrit 
Hemoglobin 
Platelet count
Red blood cell (RBC) count 
RBC morphology, if needed
White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio 
will be measured in all subjects at screening and 
subsequently if confirmed drug-induced liver 
injury (DILI) is suspected (Section 8.4.2)
Urinalysis: 
Blood
Glucose
Leucocytes
Microscopic analysis
pH 
Protein
Specific gravity
Pregnancy tests (females of childbearing potential):
Serum β-HCG (screening)
Urine β-HCG (all other visits)
Biochemistry:
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total, direct, and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
C-reactive protein 
Creatinine
Estimated glomerular filtration rate 
(Schwartz formula)
Gamma-glutamyl transferase 
Glucose
Lipase
Magnesium
Phosphorus
Potassium 
Sodium 
Triglycerides
Uric acid
For children in diapers, urine specimen collection should be attempted as part of the safety lab 
assessments, but lack of urinalysis will not constitute a protocol deviation.
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7.2.9
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass. Blood samples will 
be collected 2 to 4 hours postprandial, whenever possible, at the timepoints specified in the 
Study Schedules (Table 1 and Table 2). Plasma citrulline will not be collected from infant 
subjects. Samples may be drawn from a central line or peripheral access and processed according 
to instructions in the Laboratory Manual.
7.2.10 Antibody Assessments
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the baseline visit (day 0) and at least 14 hours after the previous 
dose at the EOT visit (week 24 or early termination); samples may be drawn from a central line 
or peripheral access. One additional sample will be collected at the EOS 4 weeks after the EOT 
(ie, week 28 or EOS).
If a blood sample tests positive for anti-teduglutide antibodies at week 28 or EOS, then the 
subject will be retested 3 months after EOT. If that sample tests positive, then the subject will be 
retested 6 months after EOT.
7.2.11 Pregnancy Testing
Any female subject of childbearing potential (Section 4.3) must have negative pregnancy tests to 
enroll or continue in the study. Pregnancy tests will be performed at screening (serum β-HCG 
testing) and at all site visits (urine β-HCG testing).
7.2.12 Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study.
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than one blood assessment 
is to be done at the same timepoint, the assessments should be combined if they require the same 
type of tube.
7.2.13 Electrocardiogram
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s) 
as indicated in the Study Schedules (Table 1 and Table 2). Electrocardiogram recordings will be 
read locally by an experienced physician. Results (normal; abnormal, not clinically significant; 
and abnormal, clinically significant with a description of the abnormality) will be recorded on 
the eCRF.
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7.2.14 Gastrointestinal-specific Testing
Gastrointestinal testing will be performed as needed for all subjects during the screening period, 
as indicated in Sections 7.2.14.1 to 7.2.14.4. Follow-up testing will be performed as needed 
according to the guidelines noted in Sections 7.2.14.1 to 7.2.14.4 and the Study Schedules (Table 
1 and Table 2).
7.2.14.1
Upper Gastrointestinal Series with Contrast
An upper GI series with small bowel follow-through (UGI/SBFT) will be performed following 
the ingestion of barium contrast material during the screening period. Results from procedures 
performed within 6 months prior to visit 1 will also be acceptable if the most recent results show 
no evidence of obstruction. If there is evidence of obstruction on the most recent UGI/SBFT 
prior to the study, this test should be performed during the screening period.
7.2.14.2
Abdominal Ultrasound
An abdominal ultrasound will be performed in subjects over 12 months of age. Results from 
procedures performed within 6 months prior to visit 1 will also be acceptable.
7.2.14.3
Fecal Occult Blood Testing
In subjects over 12 months of age, FOBT will be performed at screening, week 12, and week 24 
(EOT). Fecal occult blood testing will not be performed in infants (age 4 months through 12 
months corrected gestational age). 
Subjects with positive fecal occult blood testing results at screening or at week 24 for whom a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy. Subjects with positive fecal occult blood testing results at week 12 for which a 
cause is not identified by a physical examination will be discussed with the medical monitor or 
designee. If clinically indicated, upper endoscopy may also be performed with any colonoscopy 
or sigmoidoscopy at the discretion of the investigator.
Subjects with negative endoscopy findings at screening may enroll in the study.
Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with the medical monitor or designee, the subject is considered 
appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with the medical monitor or designee, the 
subject is considered inappropriate to be enrolled in the study.
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7.2.14.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy or sigmoidoscopy at screening. 
If the fecal occult blood testing is negative at screening and the procedure was performed within 
1 year before the screening visit (visit 1), then those prior results are acceptable for the screening 
assessment.
Children over 12 months will undergo the procedure if they test positive for FOBT at screening 
and the cause is not identified by physical examination (see Section 7.2.14.3).  
Colonoscopy/sigmoidoscopy is not to be performed for infant subjects.
Requirements for colonoscopy or sigmoidoscopy in response to positive fecal occult blood 
testing at weeks 12 or 24 are presented in Section 7.2.14.3.
7.2.15 Other Study Procedures
7.2.15.1
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/guardian 
representative in a GI-specific symptoms history diary on a daily basis. At the baseline visit, the 
investigator will review the GI-symptoms diary and summarize the findings.
7.2.15.2
Nutritional Support
Nutritional support includes PN/IV and EN. Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status, 
and safety laboratory results. Guidelines for nutritional support management and weaning 
algorithms are provided in Appendix 2 and Appendix 3 respectively.
Intake diaries will be used to collect and evaluate each subject’s nutritional support.
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7.2.15.3
Diaries
The subject/parent/guardian/study site staff will complete the appropriate fields of the PN/IV and 
EN (formula) sections of the intake diary.
Intake diary: The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:

PN/IV volume and infusion duration

EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
Output diary: Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every site visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc. The subject or parent will 
perform dipstick specific gravity tests on the first urine produced after the daily 
infusions of PN/IV support.

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first 
void after the daily PN/IV infusion to measure specific gravity.

Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency 
using the Bristol Stool Form Scale (see output diary)

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine 
and stool) as stool output and score the stool consistency using the Bristol Stool 
Form Scale (see output diary). Stool volume will be calculated using the formula: 
1 g (scale weight) = 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
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8
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS
8.1
Definitions of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 3.2. This includes events occurring during the screening phase 
of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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Note that the severity of AEs listed in Table 6 that may lead to dose interruption based on known 
risks of teduglutide will also be evaluated using the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria (Section 8.4.1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
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
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 
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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, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the 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 end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment 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, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 3.2.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
IQVIA Services Japan K.K. using the Shire Investigational and Marketed Products Pregnancy 
Report Form. 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 SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol. Note: An 
elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (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.
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8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Administration of a dose greater than the allocated dose of investigational 
product or at a frequency greater than the dosing interval specified by the protocol. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/guardian.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to IQVIA Services 
Japan K.K. within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.7) unless they result in an SAE. 
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 
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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 e-mail 
address can be found on the form (sent under separate cover). 
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed 
consent/assent is signed until the defined follow-up period stated in Section 3.2 and must be 
reported to IQVIA Services Japan K.K. within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to IQVIA Services
Japan K.K. within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
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event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent form, or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
IQVIA Services Japan K.K. is responsible for notifying the relevant regulatory 
authorities/central institutional review boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs. In addition the sponsor and/or designee is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the
teduglutide program. 
The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his or her site as required. 
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
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For AEs of special interest, IQVIA Services Japan K.K. must be informed within 24 hours of 
first awareness as per the SAE notification instructions described in Section 8.2.2 even if the 
event does not fulfill seriousness criterion.
8.4
Dose Interruption of Individual Subjects 
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to such as hospitalization and AEs, a lapse in investigational product delivery, etc.
Investigational product must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related to 
the investigational product. This does not include the presence of anti-teduglutide antibodies, 
mild injection site reactions or mild symptoms that according to the investigator do not pose 
a significant risk to the subject.

An AE listed in Table 6 that is of NCI CTCAE severity Grade 3 or 4 and considered to be 
related to the investigational product administration (see Section 8.4.1)

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The investigational product may be discontinued if the subject experiences an AE listed in Table 
6 that is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with the 
medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the DMC should be guided by the descriptions of Grade 3 and 4 events, as they 
relate to identified risks associated with the administration of teduglutide (see Table 6).
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent 
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or 
hospitalization indicated; nonemergent 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent 
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (total bilirubin >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification laboratory assessments and an 
inquiry should be made as to the presence of clinical symptoms consistent with new liver injury. 
The subject should be followed closely to determine the trajectory of the laboratory 
abnormalities and to evaluate the cause of liver injury. This evaluation may include, as clinically 
indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A immunoglobulin M [IgM], 
hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, Epstein-Barr virus 
antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (anti-nuclear, 
anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), intestinal failure 
associated liver disease, cardiovascular causes such as ischemic hepatitis, and concomitant 
hepatotoxic treatments.
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Additional evaluations may be performed at the discretion of the investigator in consultation 
with the medical monitor or designee.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
investigational product.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

At least 2 subjects develop the same event listed in Table 6 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 6 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying disease 
process.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator or investigators’ authorized site personnel must enter the information required 
by the protocol in the eCRF. A study monitor will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the eCRF will be addressed by 
the investigator or qualified site personnel. When a data discrepancy warrants correction, the 
correction will be made by the investigator or authorized site personnel. The investigator must 
verify that all data entries in the eCRF are accurate and correct. Original diary data should be 
entered into the eCRF and take precedence over data collected over the phone. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. Once a subject is enrolled, it is expected that the investigator or authorized site 
personnel will complete the eCRF entry in a timely manner following the subject’s visit.
9.2
Clinical Data Management
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US Food and Drug Administration (FDA) 21 CFR Part 11 Guidance. The 
clinical trial database will include an audit trail to document any evidence of data processing or 
activity on each data field by each user.
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will 
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Drug Safety database.
9.3
Statistical Analysis Process
The 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.
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Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
Data will be analyzed and presented by subject cohorts. The infant cohort will be analyzed in a 
manner analogous to the pediatric cohort unless specified otherwise.
All statistical analyses will be performed using SAS®.
9.4
Planned Interim Analysis and Data Monitoring Committee
9.4.1
Planned Interim Analysis
An interim analysis of subjects 1-15 years of age will be performed at the completion of their 
participation.
9.4.2
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by Shire, independent contractors hired by Shire, or members of regulatory 
agencies. The DMC may make recommendations to Shire regarding stopping, modifying or 
continuing the study; however, Shire will have the final responsibility to determine whether the 
study should be modified or temporarily or permanently stopped.
Safety and tolerability results will be evaluated by a DMC which will convene approximately 
every 3 months during the active study period (date of the first subject’s first dose to date of the 
last subject’s last dose), based on subject enrollment. The DMC review will include all 
cumulative safety data from study assessment through the end of each review period.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation.
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9.6
Study Population
Subjects are considered enrolled in the study when they meet all eligibility criteria at screening 
and eligibility criteria are confirmed at visit 2/baseline.
The ITT population is defined as any subjects who were enrolled into the study. The safety 
population is defined as the subset of ITT with subjects who received at least 1 administration of 
investigational product with any safety follow-up. The primary population analyzed for 
efficacy/PD will be the ITT population.
An additional per-protocol population analysis will also be performed as secondary/sensitivity 
analysis. The per-protocol population is defined as the subset of subjects in the ITT population 
without a major protocol deviation. Details will be prospectively defined in the final SAP prior to 
database lock.
The PK analysis population is defined as all subjects in the safety analysis population for whom 
the primary PK data are considered sufficient and interpretable.
9.7
Demographics and Baseline Characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories) will be presented, as appropriate, to 
summarize the demographic and baseline variables.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized.
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with specific histories 
will be summarized by system organ class and preferred term.
9.8
Efficacy/Pharmacodynamic Analyses
The efficacy/PD endpoints include: 

Change (absolute and percent change) from baseline in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories), separately, at each visit 

Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline 

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) 
compared to baseline

≥20% reduction in PN/IV volume at each visit 

Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, to 
week 28 (or EOS)
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
Change in hours per day and days per week of PN/IV support
No formal statistical test will be performed due the limited sample size.
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
9.9
Safety Analyses
The safety and tolerability variables include:

Adverse events, including those pertaining to GI symptoms

Body weight, height (or length), head circumference (up to 36 months of age), and trends on 
growth charts

Vital signs, including temperature, heart rate, blood pressure 

Electrocardiograms

Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis) including the 
following lab tests at all site visits and interim safety labs to detect hepatotoxicity signals: 
AST, ALT, alkaline phosphatase (ALP), and bilirubin

Urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide

GI-specific testing including colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal 
occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment-emergent AEs will be summarized by 
system organ class and preferred term. The number and percentage of subjects with AEs, SAEs, 
AEs that lead to discontinuation, investigational product-related AEs (determined by the 
investigator), and AEs that resulted in a fatal outcome will be summarized. AEs will also be 
summarized with regard to intensity and relationship to investigational product. For AEs of 
special interest, the CTCAE grading system will be used as described in Section 8.4.1.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies.
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9.10
Other Analyses
9.10.1 Pharmacokinetic Analyses
The following PK parameters will be estimated based on measured teduglutide plasma 
concentrations using a population PK modeling approach and reported separately:

Area under the concentration-time curve at steady state (AUCtau,ss)

Maximum plasma concentration at steady state (Cmax,ss)

Minimum plasma concentration at steady state (Cmin,ss)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics for PK parameters (mean, median, standard deviation, minimum and 
maximum values, geometric mean) will be calculated.
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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’s Responsibilities
10.1.1 Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee ensures that local regulatory authority requirements are met before the 
start of the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior to 
release of investigational product for shipment to the site.
10.1.2 Public Posting of Study Information
The sponsor or designee is responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries may include participating 
investigators’ names and contact information.
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.
10.1.4 Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
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10.2
Investigator’s Responsibilities
10.2.1 Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor or designee before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent/assent, inform them of the subject’s participation in the study.
10.2.2 Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will 
promptly inform the sponsor and the IRB/EC and provide them with a detailed written 
explanation. The investigator will also return all investigational product, containers, and other 
study materials to the sponsor. Upon study completion, the investigator will provide the 
sponsor, IRB/EC, and regulatory agency with final reports and summaries as required by 
international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is 
provided at all phases during the study, may be done by the sponsor, applicable contract 
research organization, investigator, or for multicenter studies, the coordinating principal 
investigator according to national provisions and will be documented in the investigator 
agreement.
10.2.3 Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms will be supplied by the sponsor or designee and should be handled 
in accordance with instructions from the sponsor.
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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 solely onto the eCRF.
All data transmitted to the sponsor or designee must be endorsed by the investigator. The study 
monitor will verify the contents against the source data per the monitoring plan. If the data are 
unclear or contradictory, queries will be sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to subject’s 
medical file, subject diaries, and original clinical laboratory reports, and imaging reports. All key 
data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the 
Pharmaceuticals and Medical Devices Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator receives from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1 Informed Consent
It is the responsibility of the investigator or designee to obtain written informed consent from 
all subjects or parents/guardians, and assent from subjects where applicable, prior to any study-
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related procedures including screening assessments. All consent and assent documentation must 
be in accordance with applicable regulations and GCP. Each subject or the subject’s parent or 
guardian, as applicable, is requested to sign and date the informed consent form/assent, or a 
certified translation if applicable, after the subject has received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent/assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent or guardian, as applicable. This document requires translation into the local 
language. Signed consent/assent forms must remain in each subject’s study file and must be 
available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/guardian of the safe, responsible storage and administration of investigational 
product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form and assent 
form where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2 Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent 
document (approved by the sponsor or their designee), relevant supporting information and all 
types of subject recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. Responsibility for coordinating with IRBs/ECs is defined in the 
investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor or designee has received 
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies 
this can be done by the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
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10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) 
which gave approval for the study to proceed. The sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11
LIST OF REFERENCES
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Kitajima, M., Shamizu, M., Wakabayashi, G., Hoshino, K., Tanabe, M. & Kawachi, S. 2013. 
Current Issues in Liver and Small Bowel Transplantation, Springer Science & Business 
Media.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D., Boctor, D., Brindle, M., Lam, V. & Robertson, M. 2011. Elements of successful 
intestinal rehabilitation. J Pediatr Surg, 46, 150-6.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Takagi, Y., Okada, A., Sato, T., Fukushima, T., Shirotani, N., Osawa, Y., Takeyama, H., 
Taniguchi, M., Takehara, H. & Mizote, H. 1995. Report on the first annual survey of 
home parenteral nutrition in Japan. Surg Today, 25, 193-201.
Takehara, H. 2001. Home parenteral nutrition for pediatric patients. Nihon Rinsho, 59 Suppl 5, 
848-51.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T.,
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
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12
APPENDICES
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
18 Dec 2015
Global
Amendment 1
27 Apr 2016
Global
Amendment 2
06 Jun 2017
Global
Amendment 3
24 Jan 2018
Global
Amendment 4
12 Jun 2018
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
Amendment Date
24 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated the emergency contact information for the study.
Emergency Contact Information
Updated the product quality complaint section to address the drug delivery 
device.
Product Quality Complaints
Revised study drug administration language for clarity.
Section 6.1.2
As requested by PMDA, updated text to specify the process for training 
parent/guardian and measures to be taken to provide oversight on study 
drug administration.
Synopsis, Table 1, Section 6.1.2.1
Clarified that the study drug administration diary can be completed by study 
site staff.
Table 1, Section 6.4, Section 7.2.15.3
Added direct bilirubin to the list of laboratory tests.
Table 5
Replaced the term “legally authorized representative” with guardian.
Throughout protocol
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
06 Jun 2017
Global
Description of Change
Section(s) Affected by Change
The Pharmacovigilance SAE Reporting fax number and email address have 
been updated. A sentence has been removed from the emergency contact 
information to eliminate a redundancy with the information provided under 
the Pharmacovigilance SAE Reporting heading (Protocol Administrative 
Change Memo #2, dated 24 Aug 2016). The title of Andrew Grimm MD 
PhD is now Medical Director and his email address has been changed.
Protocol Signature Page 
Emergency Contact Information
Urine osmolality (Protocol Administrative Change Memo #1, dated 10 Aug 
2016) and urine sodium have been removed from the list of urinalysis 
parameters to be tested. Neither parameters are needed as safety parameters 
nor required for the decision to adjust a subject’s nutritional support. 
Table 5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
06 Jun 2017
Global
Description of Change
Section(s) Affected by Change
Clarification that biological therapy prohibited during teduglutide treatment 
and within 6 months prior to the pretreatment visit refers to biological 
therapy used to treat inflammatory bowel disease.
Section 5.3
Clarification that subjects, and/or any designated person who will be 
administering the investigational product, will be trained on investigational 
product preparation and administration before the first dose of teduglutide 
or the implementation of any change in ancillary kit components.
Section 6.1.2
Language on contents of ancillary kits has been revised.
Section 6.2.1
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Age range for subjects has been specified. Subjects will be 1 year through 
15 years of age. 
Title page
Protocol signature page
Synopsis
Sections 4 and 4.1
Emergency contact information has been updated.
Emergency Contact Information
Sections 8.1.6, 8.2.2, 8.2.4 
Clarification that departing from the nutritional support adjustment 
guidelines and weaning algorithms in Appendix 2 and Appendix 3, 
respectively, will not constitute a protocol deviation. 
Synopsis
Section 3.1
Statement added that subjects who complete the study may participate in a 
long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Section 3.1
Inclusion and Exclusion criteria have been refined and clarified; there were 
no criteria added with the exception of the age of subject population which 
has been added as an inclusion criterion (was previously in introductory 
sentence).
Synopsis
Sections 4.1 and 4.2
Exclusion Criterion #11 has been updated to indicate that a subject would 
be excluded from the study if the subject had participated in a clinical study 
of experimental drug within 3 months or 5.5 half-lives of the experimental 
drug, whichever is longer.
Synopsis
Section 4.2
Efficacy/PD endpoints have been lumped together and clarified. The small 
population does not warrant primary versus secondary endpoints. The 
statistical method has been clarified.
Synopsis
Section 9.8
Safety assessments and statistical methods have been clarified. 
Synopsis
Section 9.9
Study schedule of events tables have been revised to reflect the changes to 
Table 1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
the protocol and for clarity.
Table 2
Any phone contacts may be replaced with unscheduled site visits if 
necessary.
Table 1
Table 2
Section 3.1
Requirement added that female subjects of child-bearing potential undergo 
a serum-based pregnancy test at screening.
Table 1
Table 2
Sections 4.3, 7.2.8, 7.2.11
Definition of prior and concomitant medications has been expanded to 
include invasive and diagnostic procedures.
Table 1
Table 2
Section 5
Additional information on selection of teduglutide dosing regimen and 
duration in the study has been inserted.
Section 2.1
Frequency of Data Monitoring Committee meetings has been specified.
Sections 3.1 and 9.4.1
Definition of screening period has been clarified.
Section 3.2
Inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy for symptom control has been removed from 
the list of excluded disease and illness in Exclusion Criterion #24.
Section 4.2 (Table 3)
Definition of acceptable methods of contraception has been revised to 
reflect available methods in Japan.
Section 4.3
List of prohibited prior therapy has been revised to remove experimental 
antibody treatment, as it is now included in the revised exclusion 
criterion #11.
Section 5.3
Requirement that teduglutide should be administered in the morning has 
been removed.
Section 6.2
Language on labeling, packaging, and drug accountability has been 
clarified.
Sections 6.3 and 6.4
Reviewing subject diaries has been included in the subject compliance with 
dosing check. Clarification that attempts should be made by the investigator 
to contact the sponsor or designee prior to dose interruption has been added.
Section 6.5
Requirement has been added that subjects who are re-screened must be re-
consented.
Section 7.1.1
Timeframe for a subject to be considered enrolled in the study has been 
clarified.
Sections 7.1.2 and 9.6
Demographics and other baseline characteristics have been clarified.
Section 7.2.4
Windows for PK blood collection have been extended; possibility to collect 
week 4 timepoint at any future visit if needed has been added.
Section 7.2.5
PT/INR testing has been added at screening and subsequently if confirmed 
drug-induced liver injury (DILI) is suspected thereafter.
Table 1
Table 2
Section 7.2.8
For children in diapers, urine specimen collection should be attempted as 
Table 1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
part of the safety lab assessments, but lack of urinalysis will not constitute a 
protocol deviation.
Table 2
Section 7.2.8
Timeframe of follow-up for subjects with blood samples testing positive for 
anti-teduglutide antibodies at week 28 or EOS has been clarified.
Synopsis
Table 1
Table 2
Section 7.2.10
Need for a subject with a positive fecal occult blood testing at week 12 
without a readily identifiable cause by physical examination to undergo a 
colonoscopy or sigmoidoscopy is now open to discussion with the Shire 
medical monitor or designee.
Table 1
Table 2
Section 7.2.14.3
Need for children younger than 12 years to undergo a colonoscopy or 
sigmoidoscopy if they test positive for fecal occult blood at screening and 
the cause is not identified by physical examination has been specified.
Section 7.2.14.4
GI symptoms history worksheet has been renamed GI-specific symptoms 
history diary, and details on recording and reviewing symptoms have been 
added. 
Table 1
Table 2
Section 7.2.15.1
“Other nutrition (regular diet and drink)” has been removed from the Intake 
diary.
Section 7.2.15.2
Output diary data collection will continue to occur over a 48-hour period of 
PN/IV and EN stability before every site visit. Between site visits, the 
output diary collection will only be required within 1 week of implementing 
a change in the PN/IV prescription.
Table 1
Table 2
Section 7.2.15.3
Severity categorization has been updated to specify that the severity of AEs 
listed in Table 6 that may lead to dose interruption based on known risks of 
teduglutide will also be evaluated using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grading criteria.
Section 8.1.1
Definition of an overdose to teduglutide has been revised.
Section 8.1.7
Adverse events of special interest have been redefined and procedures for 
reporting them have been added.
Section 8.3
More information has been provided on criteria for dose interruption of 
individual subjects. Dose discontinuation has been made absolute for an AE 
known to be a risk associated with teduglutide administration (Table 6) that 
is of NCI CTCAE severity ≥Grade 3 and considered to be related to 
investigational product; cases of severe hypersensitivity that are determined 
to be related to investigational product; DILI that is related to 
investigational product; and pregnancy. SAEs related to investigational 
product are potential but not absolute reasons for dose discontinuation.
Sections 8.4, 8.4.1, and 8.4.2
Criteria for DILI have been added.
Section 8.4.2
Criteria for early termination of the study have been clarified.
Section 8.5
Clarification that original diary data should be entered into the eCRF and 
take precedence over data collected over the phone.
Section 9.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
27 Apr 2016
Global
Description of Change
Section(s) Affected by Change
Definition of PK analysis population has been added.
Section 9.6
Pharmacokinetic analyses methods and parameters have been clarified.
Synopsis
Section 9.10.1
Protocol history has been added in Appendix 1.
Appendix 1
Guidelines for nutritional support management during the study have been 
clarified.
Appendix 2
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Appendix 2
Guidelines for Nutritional Support Management During the Study 
(SHP633-302)
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should be considered for managing nutritional support 
(PN/IV and EN [PN/EN]) in terms of volume and calories during the treatment period: 

Growth trajectory, including weight, height (or length), and head circumference (for children 
up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen/creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Form Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food and fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.
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Appendix 3
Weaning Algorithms 
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet-trained and in Diapers
Figure A-2
Subjects Who Are Toilet-trained and Not in Diapers
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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment
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Appendix 4
Monitoring Personnel
Shire Japan K.K.
Global Clinical Development Operations
1-8-2 Marunouchi, Chiyoda-ku, Tokyo, 100-000, Japan
Name: 
Contact info: TEL: 
Name: 
aki
Contact info: TEL: 
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT02980666 
Study Title: 
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 4 Months Through 15 
Years, With Short Bowel Syndrome Who Are Dependent on Parenteral 
Support 
Study Number: 
SHP633-302 
SAP Version and Date: 
Version 1.0:  
 
17 Apr 2019 
PK Analysis Plan: 
13 Sep 2019 
For non-commercial use only


 
Statistical Analysis Plan 
 
PROTOCOL SHP633-302 
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Document: 
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Version Date: 
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Copyright © IQVIA. All rights reserved. 
The contents of this document are confidential and proprietary to IQVIA. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
SHP633-302 
A 24-WEEK SAFETY, EFFICACY, PHARMACODYNAMIC, AND PHARMACOKINETIC 
STUDY OF TEDUGLUTIDE IN JAPANESE PEDIATRIC SUBJECTS, AGED 4 MONTHS 
THROUGH 15 YEARS, WITH SHORT BOWEL SYNDROME WHO ARE DEPENDENT ON 
PARENTERAL SUPPORT 
 
 
 
 
 
AUTHOR:
VERSION NUMBER AND DATE: FINAL 1.0, 17APR2019 
 
 
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Statistical Analysis Plan 
PROTOCOL SHP633-302 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final 1.0 {Dated 17Apr2019) for Protocol SHP633-302. 
, Name 
Signature 
I Date (DDMMMYYYY) 
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Company: 
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Upon review of this document, the undersigned approves this version of the Statistical Analysis 
Plan, authorizing that the content is acceptable for the reporting of this study. 
__ 
Approved By: 
I
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Position: 
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PROTOCOL SHP633-302 
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MODIFICATION HISTORY 
 
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prohibited. 
TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS .............................................................................................................. 8 
2. INTRODUCTION AND BACKGROUND INFORMATION .......................................................... 9 
2.1. 
Study Design ............................................................................................................................................ 9 
2.2. 
Objective ............................................................................................................................................... 10 
2.2.1. 
Efficacy/Pharmacodynamic Assessments .................................................................................................10 
2.2.2. 
Safety Assessments ..................................................................................................................................10 
3. DETERMINATION OF SAMPLE SIZE ........................................................................................ 11 
4. UNBLINDING PROCEDURES ....................................................................................................... 11 
5. DATA MANAGEMENT ................................................................................................................... 11 
6. STATISTICAL/ANALYTICAL ISSUES ........................................................................................ 11 
6.1. 
General Methodology ............................................................................................................................ 11 
6.2. 
Adjustments for Covariates/Prognostic Variables ................................................................................... 13 
6.3. 
Handling of Dropouts or Missing Data .................................................................................................... 13 
6.4. 
Interim Analyses and Data Monitoring ................................................................................................... 14 
6.5. 
Multicenter Studies ................................................................................................................................ 14 
6.6. 
Multiple Comparisons/Multiplicity ......................................................................................................... 14 
6.7. 
Active-Control Studies Intended to Show Equivalence ............................................................................ 14 
6.8. 
Examination of Subgroups ...................................................................................................................... 14 
7. ANALYSIS POPULATIONS AND VISITS ................................................................................... 14 
7.1. 
Screened Population .............................................................................................................................. 15 
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7.2. 
Intention-to-treat (ITT) Population ......................................................................................................... 15 
7.3. 
Per Protocol (PP) Population .................................................................................................................. 15 
7.4. 
Safety Population ................................................................................................................................... 15 
7.5. 
Pharmacokinetic (PK) Population............................................................................................................ 16 
7.6. 
Windowing Visits ................................................................................................................................... 16 
8. STUDY SUBJECTS ........................................................................................................................... 16 
8.1. 
Subjects Screened .................................................................................................................................. 16 
8.2. 
Study Analysis Populations ..................................................................................................................... 16 
8.3. 
Protocol Deviations ................................................................................................................................ 16 
8.4. 
Disposition of Subjects ........................................................................................................................... 17 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................................... 17 
9.1. 
Analysis of Demographic and Other Baseline Characteristics ................................................................... 17 
10. MEASUREMENTS OF TREATMENT COMPLIANCE .............................................................. 19 
11. EFFICACY/PHARMACODYNAMIC EVALUATION ................................................................. 20 
11.1. 
Analysis of Efficacy and Pharmacodynamic Variables .......................................................................... 20 
12. PHARMACOKINETIC EVALUATION ......................................................................................... 22 
13. SAFETY EVALUATION .................................................................................................................. 23 
13.1. 
Extent of Exposure.............................................................................................................................. 23 
13.2. 
Adverse Events ................................................................................................................................... 23 
13.3. 
Clinical Laboratory Evaluation ............................................................................................................. 24 
13.4. 
Vital Signs ........................................................................................................................................... 26 
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13.4.1. 
Z-scores of height for age and weight for age for children 1-15 years of age ......................................29 
13.4.2. 
Z-scores of length for age and weight for age for infants 4-12 months corrected gestational age .....29 
13.4.3. 
Z-scores of head circumference for all study subjects ≤36 months of age ...........................................29 
13.4.4. 
Z-scores of BMI for children 2-15 years of age .....................................................................................29 
13.4.5. 
Z-scores of weight for length for infants ..............................................................................................30 
13.5. 
ECG Variables ..................................................................................................................................... 30 
13.6. 
Physical Examination .......................................................................................................................... 30 
13.7. 
Antibodies to Teduglutide .................................................................................................................. 30 
13.8. 
Gastrointestinal-Specific Testing ......................................................................................................... 30 
13.9. 
Fecal and Urine Output ....................................................................................................................... 30 
13.10. 
Prior and Concomitant Medications .................................................................................................... 31 
14. CHANGES IN THE STATISTICAL METHODOLOGY PRESENTED IN THE PROTOCOL 32 
15. GENERAL PROGRAMMING INFORMATION ........................................................................... 32 
15.1. 
General .............................................................................................................................................. 32 
15.2. 
Format of Tables/Listings .................................................................................................................... 32 
15.3. 
Data Formats ...................................................................................................................................... 33 
16. TABLE, FIGURE AND DATA LISTING SHELLS ....................................................................... 34 
16.1. 
Table Shells ........................................................................................................................................ 34 
16.2. 
Figure Shells ....................................................................................................................................... 34 
16.3. 
Data Listing Shells ............................................................................................................................... 34 
17. REFERENCES ................................................................................................................................... 34 
 MARKEDLY ABNORMAL LABORATORY CRITERIA ......................... 35 
APPENDIX 1.
 L, M AND S VALUES OF HEIGHT, BODY WEIGHT, BMI AND HEAD 
APPENDIX 2.
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CIRCUMFERENCE FOR AGE FOR JAPANESE ...................................................................... 37 
 MEDDRA TERMS CORRESPONDING TO EACH GROUPING OF 
APPENDIX 3.
ADVERSE EVENTS OF SPECIAL INTEREST ........................................................................... 42 
 
 
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1. LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
AST 
Aspartate Aminotransferase  
BMI 
Body Mass Index  
CDC 
Centers for Disease Control and Prevention  
CTMS 
Clinical Trial Management System 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EN 
Enteral Nutrition  
EOS 
End of Study  
EOT 
End of Treatment  
GI 
Gastrointestinal 
HLGT 
Higher Level Group Term 
ICH 
International Conference on Harmonisation 
ITT 
Intention-to-Treat  
MedDRA 
Medical Dictionary for Regulatory Activities  
MOS 
Months 
NA 
Not Applicable 
PD 
Pharmacodynamics  
PK 
Pharmacokinetic 
PN/IV 
Parenteral Nutrition/Intravenous Fluid  
PP 
Per Protocol 
PT 
Preferred Term  
SAE 
Serious Adverse Event 
SAF 
Safety  
SAP 
Statistical Analysis Plan  
SBS 
Short Bowel Syndrome  
SE 
Standard Error 
SI 
Standard International 
SOC 
Standard of Care  
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
UGI/SBFT 
Upper GI series with Small Bowel Follow-Through 
ULN 
Upper Limit of Normal 
WHODD 
WHO Drug Dictionary  
YRS 
Years 
 
 
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2. INTRODUCTION AND BACKGROUND INFORMATION 
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for Protocol SHP633-302. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
Pharmacokinetic analysis will be detailed in a separate analysis plan. 
This statistical analysis plan (SAP) is based on protocol amendment 4, dated 12 June 2018. 
2.1. STUDY DESIGN 
This will be an open-label, 24-week study, in which subjects will receive 0.05 mg/kg/day of 
teduglutide. The study population will include 2 cohorts: infants 4-<12 months corrected 
gestational age and children 1-15 years of age. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. Attempts should be made to limit the screening period to 4 weeks. 
After screening, the 24-week treatment period will consist of visits at baseline, weekly for the 
first 2 weeks, and then every other week through week 12. For the remainder of the treatment 
period, visits at the sites will be conducted every 3 weeks. Scheduled telephone contacts will 
be made on all other weeks during the treatment period. At all site visits and during telephone 
contacts, safety will be monitored and nutritional support will be reviewed and adjusted as 
needed. The end of study (EOS) visit will be scheduled at week 28, 4 weeks following end of 
treatment (EOT). Weekly telephone contact will be made during the interim weeks from EOT 
to EOS to monitor safety and any changes in nutritional support.  
To maintain consistency across all centers, all attempts should be made to follow the 
nutritional support adjustment guidelines and weaning algorithms (developed with SBS expert 
input and provided in the protocol) for decisions regarding parenteral nutrition/intravenous 
fluids (PN/IV) support reduction and advances in enteral feeds based on weight gain, urine, 
and stool output in the setting of clinical stability. Any departure from the nutritional support 
adjustment guidelines and weaning algorithms will not constitute a protocol deviation. 
A schematic representation of the study design is displayed in Figure 1. The study schedule of 
events can be found in Table 1 and Table 2 of the protocol. 
Figure 1 
Study Diagram 
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2.2. OBJECTIVE 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy and 
pharmacodynamics, and pharmacokinetics of teduglutide in pediatric subjects (4 months 
through 15 years of age) with short bowel syndrome (SBS) who are dependent on parenteral 
support. 
2.2.1. 
EFFICACY/PHARMACODYNAMIC ASSESSMENTS 
The efficacy/pharmacodynamic endpoints include:  
• Change (absolute and percent change) from baseline in PN/IV support (volume and calories), 
citrulline (only for the cohort of children 1-15 years of age), and enteral nutritional support 
(volume and calories), separately, at each visit  
• Reduction in PN/IV volume of at least 20% at week 24 (or EOT) compared to baseline  
• 100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or EOT) 
compared to baseline 
• ≥20% reduction in PN/IV volume at each visit  
• Change (absolute and percent change) from week 24 (or EOT) in PN/IV support (volume and 
calories), citrulline (only for the cohort of children 1-15 years of age), and enteral nutritional 
support (volume and calories), separately, to week 28 (or EOS) 
• Change in hours per day and days per week of PN/IV support 
2.2.2. 
SAFETY ASSESSMENTS 
Safety and tolerability will be assessed by evaluating the following:  
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• Adverse events, including those pertaining to GI symptoms.  
• Physical examinations, including body weight, height (or length), head circumference (up to 
36 months of age), and trends on growth charts  
• Vital signs, including temperature, heart rate, blood pressure 
• Electrocardiograms (ECGs) 
• Laboratory safety data (ie, biochemistry, hematology, coagulation, urinalysis) 
• Urine output 
• Fecal output (by volume or number of bowel movements per day)   
• Antibodies to teduglutide 
• For children 1 to 15 years of age: GI-specific testing including colonoscopy or sigmoidoscopy, 
abdominal ultrasound, fecal occult blood testing, upper GI series with small bowel follow-
through (UGI/SBFT) 
• For infants 4 to <12 months corrected gestational age: UGI/SBFT 
3. DETERMINATION OF SAMPLE SIZE 
The sample size is determined based on enrollment feasibility of this orphan population in 
children in Japan, rather than power calculation. 
4. UNBLINDING PROCEDURES 
No unblinding procedures apply as this is an open-label study. 
5. DATA MANAGEMENT 
IQVIA is responsible for data management activities for this study. Details about data 
management, including the eCRF design, the EDC system, data validation and discrepancy 
management, reconciliation of data from different sources, and electronic data transfer, are 
included in the Data Management Plan for this study. 
6. STATISTICAL/ANALYTICAL ISSUES 
6.1. GENERAL METHODOLOGY 
All statistical procedures will be completed using SAS version 9.4 or later. 
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Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data. 
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. Standard errors (SE) will be displayed for the efficacy tables, and 
body weight, height (or length), BMI, head circumference and weight for length. For categorical 
variables, descriptive statistical summaries will include number of subjects and percentages. 
For summary purposes, the baseline value will be defined as the last available pre-dose value. 
Scheduled visits will be summarized as provided in the electronic case report forms (eCRFs). 
An End of Treatment (EOT) time point, defined as the last determination of endpoint or last 
available measurement after the date of first dose during the 24-week treatment period will be 
analyzed in addition to the scheduled visits. Similarly, an End of Study (EOS) time point will be 
defined as the last determination of endpoint or last available measurement after the EOT 
during the 4-week follow-up period. Unscheduled measurements will not be included in by-visit 
summaries, but can contribute to the EOT/EOS value where applicable. 
Study Day will be calculated as follows: 
• If the date of the evaluation is on or after the first day of study medication then:  
                Study Day = (date of the evaluation – first day of study medication) + 1. 
• If the date of the evaluation is prior to the first day of study medication then:  
                Study Day = (date of the evaluation – first day of study medication). 
Datasets and listings will include data collected at unscheduled visits. Data collected at 
unscheduled visits will not be included in summaries by timepoint or visit unless specified 
otherwise. 
Data will be analyzed and presented by subject cohorts: 
• Infants: 4-<12 months corrected gestational age 
• Children: 1-15 years of age 
The corrected gestational age as captured on the demographics page of the eCRF will be 
used to determine the cohort a subject belongs to, i.e., if the corrected gestational age is <12 
months, the subject will be in the infant cohort. The infant cohort will be analyzed in a manner 
analogous to the cohort of children 1-15 years of age unless specified otherwise. 
Analyses will be done for all subjects, and subset of subjects who began treatment after 
protocol amendment 3.0. Main conclusions will be based on subjects who began treatment 
after implementation of protocol amendment 3.0. 
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6.2. ADJUSTMENTS FOR COVARIATES/PROGNOSTIC VARIABLES 
No adjustments for covariates are planned in the statistical analyses. 
6.3. HANDLING OF DROPOUTS OR MISSING DATA 
All subjects in the analysis population defined in Section 7 will be included in the associated 
analyses. 
No imputation for missing data (e.g., last observation carried forward [LOCF]) will be applied 
except for the partial dates for adverse events and prior/concomitant medications. 
Details on how to handle partial dates for adverse events and prior/concomitant medications 
are described below. 
Complete dates will be imputed from partial dates of adverse events and medications solely 
for the purpose of defining treatment emergence for adverse events and prior/concomitant 
status for medications (Imputed dates will not be presented in the listings). Dates will be 
defined using the hierarchy of derivations below. 
Adverse event or medication start date (references to month and year are the month and year 
of the start date): 
1. If year and month are known, and it is the month and year of the first dose date, use the 
first dose date. 
2. If year and month are known, and it is not the month and year of the first dose date, use 
the first day of the month. 
3. If only year is known, and it is the year of the first dose date, use the first dose date. 
4. If only year is known, and it is not the year of the first dose date, use the first day of the 
year (1st January). 
5. Should any of the previous start dates created be after a complete stop date provided, 
use the stop date as the start date, instead of the date that would otherwise be created. 
6. For medication start date, if “Before Informed Consent” is ticked then use the date of 
informed consent. 
7. Otherwise, if start date is unknown leave as missing. 
Adverse event or Medication stop date (references to month and year are the month and year 
of the stop date): 
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1. If year and month are known, use the last day of the month. 
2. If only year is known, use the last day of the year (31st December). 
3. Otherwise, if stop date is unknown leave as missing. 
6.4. INTERIM ANALYSES AND DATA MONITORING 
An interim analysis of subjects 1-15 years of age will be performed at the completion of their 
participation. 
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) which 
will convene approximately every 3 months during the active study period (date of the first 
subject’s first dose to date of the last subject’s last dose), based on subject enrollment. The 
DMC review will include all cumulative safety data from study assessment through the end of 
each review period. 
6.5. MULTICENTER STUDIES 
Because a small number of subjects are expected at each center, data from all centers will be 
pooled. 
6.6. MULTIPLE COMPARISONS/MULTIPLICITY 
Not Applicable. 
6.7. ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE 
Not applicable. 
6.8. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be conducted given the small number of patients in this study. 
7. ANALYSIS POPULATIONS AND VISITS 
If there are two populations that consists of the same patients, the analysis planned to be 
conducted for the two populations will only be conducted once for the intention-to-treat 
population and the analysis for the latter population (per protocol, safety and/or 
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pharmacokinetic) in this list will not be generated since it will be the same outputs.   
7.1. SCREENED POPULATION 
All subjects who provided signed Informed Consent Form will be included in the Screened 
population. 
7.2. INTENTION-TO-TREAT (ITT) POPULATION 
The intention-to-treat (ITT) population will consist of all subjects who are enrolled into the 
study. Subjects are considered enrolled in the study when they meet all eligibility criteria at 
screening and eligibility criteria are confirmed at visit 2/baseline. The ITT population will be the 
primary analysis population analyzed for efficacy/PD endpoints. 
7.3. PER PROTOCOL (PP) POPULATION 
The per protocol (PP) population will contain all subjects in the ITT population who complete 
the study treatment period without incidence of any major protocol deviations or other 
situations that could potentially affect the efficacy conclusion of the study.    
Major protocol deviations leading to exclusion from the PP population include:   
• Subjects with no detectable teduglutide post dose in the blood as part of PK assessments, or 
subjects who lack all PK assessments 
• Missing baseline and/or Week 24 efficacy data 
• Non-compliance to study drug as defined in Section 10 
Major protocol deviations will be programmatically derived. 
The Per Protocol population will be the sensitivity analysis population analyzed for primary 
efficacy endpoints. Reasons for exclusion from the PP population will be summarized for the 
ITT population and presented in the data listings. 
7.4. SAFETY POPULATION 
The Safety population will consist of all subjects in the ITT population who receive at least 1 
administration of investigational product with any safety follow-up. All safety analyses will be 
conducted on this population, unless otherwise specified. 
All collected data will be included in the listings. 
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7.5. PHARMACOKINETIC (PK) POPULATION 
The PK population is defined as all subjects in the Safety population for whom the primary PK 
data are considered sufficient and interpretable. 
7.6. WINDOWING VISITS 
Although there is a visit window from 2 to 4 days around the expected visit date, nominal visits 
will be used for the per-visit analyses. Therefore, no windowing of visits by study day will be 
done for data obtained at the scheduled visits. For subjects who withdraw from the study 
prematurely, if the early termination visit falls into the window of a scheduled visit as defined in 
the protocol, the early termination visit is also summarized for that scheduled visit, unless the 
scheduled visit already took place. 
8. STUDY SUBJECTS 
8.1. SUBJECTS SCREENED 
The number of subjects screened will be presented. 
8.2. STUDY ANALYSIS POPULATIONS 
The number and percent of subjects in each study analysis population (i.e., ITT, PP, Safety 
and PK) will be presented for the Screened population. 
8.3. PROTOCOL DEVIATIONS 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to severity categories (“minor”, “important” and 
“priority”) and provided as part of the CTMS transfer to Biostatistics. Protocol deviations will be 
summarized for the ITT population. A listing of protocol deviations by subject will be presented 
in the data listings. 
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8.4. DISPOSITION OF SUBJECTS 
For the ITT, PP, PK and Safety populations, study enrollment as well as treatment and study 
completion status will be summarized. The reason for discontinuing treatment and/or study 
early will also be presented. 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
9.1. ANALYSIS OF DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The baseline and demographic characteristics will be summarized with descriptive statistics 
defined in Section 6.1 for the ITT and Safety populations. Demographic and baseline 
characteristics to be presented include: 
• Age at informed consent date in years for the cohort of children 1-15 years of age. Age in 
years will be rounded to 1 decimal place for reporting. 
• Chronological (actual) age at informed consent date in months for the infant cohort. 
Chronological age in months will be rounded to 1 decimal place for reporting. 
• Corrected gestational age at informed consent date in months for the infant cohort. Corrected 
gestational age in months will be rounded to 1 decimal place for reporting.  
• Sex 
• Race 
• Ethnicity 
• Height or length for age Z-score at Baseline  
• Weight for age Z-score at Baseline  
• Head Circumference for age Z-score at Baseline (only for subjects who are <= 36 months of 
age) 
• BMI for age Z-score at Baseline only for children 2-15 years of age 
• Weight for length Z-score at Baseline only for the infant cohort 
BMI, Z-score of weight, height or length, BMI and head circumference for age as well as 
weight for length Z-score will be calculated based on the method described in Section 13.4. Z-
scores will be rounded and presented to 2 decimal places. 
The following Short Bowel Syndrome History information collected at the Screening visit will be 
summarized with descriptive statistics defined in Section 6.1 for the ITT and Safety 
populations: 
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• Duration of SBS 
• Primary reason for the diagnosis of SBS (necrotizing enterocolitis, midgut volvulus, intestinal 
atresia, gastroschisis, trauma, cancer, crohn’s disease, long-segment hirschprung disease, 
other) 
• Secondary reason for the diagnosis of SBS (Y/N), secondary reason (necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, gastroschisis, trauma, cancer, crohn’s 
disease, long-segment hirschprung disease, other) 
• stoma (Y/N), stoma type (jejunostomy, ileostromy, colostomy, other) 
• Remaining colon (Y/N), estimated percent of colon remaining, and colon in continuity (Y/N) 
• Colonoscopy in the last 12 months (Y/N/NA) 
• Total estimated remaining small intestinal length (cm) 
• Presence of the distal/terminal ileum (Y/N) and ileocecal valve (Y/N) 
• Method to determine remaining anatomy length (surgery, radiology, other) 
For children 1-15 years of age, duration of SBS in years will be calculated as (Date of informed 
consent form signed – Date of diagnosis of SBS +1) / 365.25 and rounded to 1 decimal place 
for reporting. 
For infants, duration of SBS in months will be calculated as (Date of informed consent form 
signed – Date of diagnosis of SBS +1) / (365.25/12) and rounded to 1 decimal place for 
reporting. 
The following Parenteral Nutrition/Intravenous History and Enteral Nutrition (EN) History 
information collected at the Baseline visit will be summarized with descriptive statistics defined 
in Section 6.1 for the ITT and Safety populations: 
• Years or months since start of PN/IV dependency 
• Current use of EN (Y/N), reason not taking EN (following a regular diet, other) 
• Years or months since start of EN dependency 
For children 1-15 years of age, years since start of PN/IV dependency will be calculated as 
(Date of informed consent form signed – Start date of PN/IV dependency +1)/365.25.  
For infants 4-12 months corrected gestational age, months since start of PN/IV dependency 
will be calculated as (Date of informed consent form signed – Start date of PN/IV dependency 
+1)/ (365.25/12).  
Years and months since start of EN dependency will be calculated in a similar manner but 
using the start date of EN dependency. Both these durations will be rounded to 1 decimal 
place for reporting. 
The following Parenteral Nutrition/Intravenous History information collected at baseline will be 
summarized in the by-visit efficacy tables and listed: 
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• Prescribed weekly PN/IV volume 
• Prescribed weekly PN/IV calories 
• Prescribed number of days per week of PN/IV 
• Prescribed average number of hours per day of PN/IV 
• Prescribed weekly EN volume 
• Prescribed weekly EN calories 
 
The following Gastrointestinal Symptoms History collected at the Baseline visit will be 
summarized for the ITT and Safety populations based on categories of not present, mild, 
moderate, and severe, with clinical significance also summarized where the event is present: 
• Abdominal/belly pain 
• Nausea/feeling queasy 
• Vomiting/throw up 
• Heartburn/reflux/spit up 
• Gas/bloating 
• Diarrhea/loose stool  
• Constipation/very hard stool 
 
Partial dates for the date of diagnosis of SBS and start of PN/EN dependency will use the first 
day of the month if only the day is missing. If both the day and month are missing, the first day 
of January will be used. 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Investigator verbatim as well as preferred terms and system organ class 
will be included in the listings. The medical and surgical history will be summarized by system 
organ class (SOC) and preferred term (PT) within system organ class for the Safety 
population, with SOC sorted alphabetically and PT within SOC by descending incidence. 
10. MEASUREMENTS OF TREATMENT COMPLIANCE 
Percent compliance will be calculated as 100 times the number of days the study treatment 
was administered per instructions by the number of days on treatment. Number of days on 
treatment is calculated as (last dose date – first dose date +1). The information whether the 
study treatment was administered per instructions is captured on the study drug administration 
daily diary. Administration of the study treatment by the investigator will be considered per 
instructions. Subjects will be considered compliant overall for study medication if the 
calculated compliance is ≥ 80%. Overall treatment compliance will be presented for both 
percent compliance calculations using descriptive statistics and the number and percentage of 
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subjects who are ≥ 80% compliant for the ITT and Safety populations. Treatment compliance 
by visit will not be calculated. 
11. EFFICACY/PHARMACODYNAMIC EVALUATION 
11.1. ANALYSIS OF EFFICACY AND PHARMACODYNAMIC VARIABLES 
Primary efficacy/pharmacodynamic analyses will be conducted on the ITT population. The PP 
population will be used for sensitivity analysis purpose. 
PN/IV and EN support will be reported in both subject diary data and the investigator-
prescribed data in the eCRF. Diary and prescribed PN/IV and EN volume/calories will be 
normalized to weight in order to facilitate comparability of results across patients in this 
pediatric population. Data will be summarized at all scheduled visits during the 24-week 
treatment period and the follow-up period (Week 25, 26, 27, 28). An End of Treatment (EOT) 
time point will also be added. Data collected at unscheduled time points will be included in the 
listings but will not be summarized at those unscheduled time points. 
Prescribed data are the most recent PN/IV or EN prescription (from either baseline or 
prescription adjustments) prior to or on the date of visit, captured in the PN/IV or EN history 
and PN/IV or EN adjustments eCRFs.  
Average daily values normalized to weight will be calculated for PN/IV volume, PN/IV calories, 
EN volume and EN calories as follows: 
Average Prescribed daily value = (prescribed weekly value / 7) / last available body weight 
prior to or on the date of visit 
Calculation of post-baseline diary PN/IV and EN parameters (including hours per day and days 
per week of PN/IV support) will be based on the daily support recorded in subjects’ diaries 
within 7 days prior to the date of each scheduled post-baseline visit. Baseline diary PN/IV and 
EN parameters will be calculated using the most recent 14 days of diary data collected prior to 
the first dose, and week 1 calculations will not use any pre-baseline diary data.  
Average daily values normalized to weight will be calculated for PN/IV volume, PN/IV calories, 
EN volume and EN calories as follows: 
Average diary daily value = (sum of non-missing daily values in the diary / number of days with 
non-missing values) / last available body weight prior to the visit 
If more than 2 days’ values in a week are missing, the average daily value will not be 
calculated and will be assigned as missing. If more than 5 days’ values in two weeks before 
baseline visit, the baseline values are missing. These missing data handling rules will be used 
to calculate all other diary average diary parameters, including PN/IV calories, PN/IV hours per 
day, PN/IV days per week, EN volume, and EN calories. 
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Percent reduction in weight-normalized diary and prescribed PN/IV volume from baseline at 
the scheduled visit will be calculated using the formula below:  
% reduction in PN/IV volume at the visit = [(average daily value at the scheduled visit - 
average daily value at baseline) / average daily value at baseline] * 100  
Percent reduction calculation will be performed on both diary and prescribed PN/IV volume 
data. 
Change and percent change from baseline in PN/IV and EN support 
The absolute and percent change from baseline in average daily values for PN/IV and EN 
support (volume and calories) to each scheduled visit during the 24-week treatment period, as 
well as at EOT and the follow-up period (Week 25, 26, 27, 28), will be presented using 
descriptive statistics defined in Section 6.1. For EN summary, change from baseline will only 
be calculated for subjects who took any EN at baseline. 
Mean ± SE plots of percent change in PN/IV and EN support (volume and caloric intake) will 
be generated. 
Plots of PN/IV and EN support (volume and caloric intake) by visit will be presented for each 
individual subject in the ITT population. 
95% confidence intervals of the mean will be generated for Week 20 and Week 24/EOT. 
 
Change and percent change from baseline in citrulline 
The absolute and percent change in citrulline from baseline to each scheduled visit during the 
24-week treatment period, as well as at EOT and the follow-up period (Week 28), will be 
presented using descriptive statistics defined in Section 6.1 for the cohort of children 1-15 
years of age. 
≥ 20% Reduction in PN/IV volume at each study visit 
PN/IV volume reduction at each study visit compared to baseline will be calculated using 
average daily values. The number and percentage of subjects who achieve at least a 20% 
reduction in PN/IV volume will be presented at each scheduled visit during the 24-week 
treatment period, as well as at EOT and the follow-up period (Week 25, 26, 27, 28). 
Complete weaning off PN/IV support at EOT 
A subject will be considered to have achieved independence from PN/IV support (completely 
weaned off PN/IV) if the investigator prescribes no PN/IV (volume and calories) and there is no 
use of PN/IV (volume and calories) recorded in the subject diary during the 7 days prior to 
EOT. The number and percentage of subjects who completely wean off PN/IV support up to 
EOT will be presented. A listing will present the study week when complete wean off was first 
achieved for these subjects who completely wean off PN/IV support at EOT. 
Change and percent change from EOT in PN/IV support, citrulline, EN support at EOS 
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The absolute and percent change from EOT to EOS in average daily values for PN/IV and EN 
support (volume and calories) as well as citrulline (only for the cohort of children 1-15 years 
age) will be presented using descriptive statistics defined in Section 6.1. If subject has 
weaned-off PN/IV or EN at EOT, change from EOT for those parameters will not be calculated. 
Change and percent change from baseline in hours per day and days per week of PN/IV 
support  
Change and percent change from baseline in hours per day and days per week of PN/IV 
support to each visit during 24-week treatment period, as well as at EOT and the follow-up 
period (Week 25, 26, 27, 28), will be presented using descriptive statistics defined in Section 
6.1. 
Hours per day of diary PN/IV support for all visits except the baseline visit will be calculated as 
follows:  
Hours per day of diary PN/IV support = (sum of hours per day for each day that PN/IV intake 
data is recorded within the 7 days prior to the visit / number of days that PN/IV hours per day 
data is recorded within the 7 days prior to the visit) 
Prescribed PN/IV hours per day for each visit (including baseline) will be taken from the most 
recent prescription data prior to or at that visit. 
Days per week of diary PN/IV support for all visits except the baseline visit will be calculated 
as follows:  
Days per week of diary PN/IV support = (number of days with non-zero values for PN/IV 
volume within the 7 days prior to the visit / number of days for which any PN/IV intake data is 
recorded within the 7 days prior to the visit) * 7  
For the week 1 visit, data prior to the baseline visit will not be used for the calculation. 
12. PHARMACOKINETIC EVALUATION 
The pharmacokinetic (PK) concentration data will be summarized on the PK population for the 
protocol scheduled sampling time points: 
• Baseline: 0-hour (pre-dose), 1-hour post-dose and 6-hour post-dose 
• Week 4: 0-hour (pre-dose), 2-hour post-dose and 4-hour post-dose 
Descriptive statistics of PK concentration (mean, standard deviation, coefficient of variation 
(CV) % mean, geometric mean, CV (%) geometric mean, median, minimum and maximum 
values) will be calculated at each time point. A listing for PK concentration data will also be 
provided. 
The PK parameters will be derived and estimated based on measured teduglutide plasma 
concentrations using a population PK modeling approach by a Takeda designated vendor in 
accordance with the PK SAP. 
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13. SAFETY EVALUATION 
All safety evaluations will be conducted on the Safety population. By-visit summaries will 
include all protocol scheduled visits during the 24-week treatment period, EOT and Week 28 
visit. 
13.1. EXTENT OF EXPOSURE 
The extent of exposure is defined as the number of days on treatment, 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. The number and 
percentages of subject will be tabulated for extent of exposure categorized into weeks (<4, 4-
<12, 12-<24 and ≥24). Exposure summaries will be presented for the ITT and Safety 
populations. 
The information related to the study drug training provided by the study physician will be listed 
for all subjects in the Safety population. 
13.2. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA. Investigator verbatim as well as preferred 
term and system organ class will be included in the listings. 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens 
or intensity increases during or after receiving the study medication. AEs with an unknown 
date of onset and a stop date after the start of the study period or unknown will be included as 
treatment emergent AEs. Any AE with a start date equal to the date of first dose, where the 
time of the AE cannot definitively place the start of the AE prior to the first dose, will be 
considered treatment emergent. If any AE records contain only partial dates, these will be 
handled by imputation, as described in Section 6.3. 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 TEAE (Y/N), severity of TEAEs (any and highest category), investigator assessment of 
relationship of TEAEs to study treatment, treatment emergent serious AEs (TESAEs), severity 
of TESAEs, investigator assessment of relationship of TESAEs to study treatment, TEAEs 
leading to death, TEAEs leading to discontinuation, and TEAEs of special interest. 
Treatment emergent AEs will be summarized using number and percentage of subjects. 
Subject incidence for AEs within each SOC and PT will be presented, unless otherwise 
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specified. The number of events will also be summarized. Categories summarized will be the 
same as those summarized in the overview tabulations, except that no summary table will be 
provided for TEAEs leading to death. Presentation by SOC and PT will present SOC sorted 
alphabetically and PT within SOC by descending incidence. 
Summaries of TEAEs, TEAEs by relationship, TESAEs and TESAEs by relationship will also 
be presented by PT. These presentations will be sorted by descending incidence. 
For the summaries described above, TEAEs with a missing severity will be classified as 
severe and TEAEs with a missing relationship to study drug will be regarded as related to 
study drug. 
In addition, AEs of special interest will be considered. An AE of special interest is an AE 
(serious or nonserious) of scientific and medical concern specific to the sponsor’s product or 
program. The AEs of special interest will include the following groupings: 
• Growth of pre-existing polyps of the colon 
• Benign neoplasia of the GI tract including the hepatobiliary system 
• Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system) 
The MedDRA terms corresponding to each grouping of events of special interest are included 
in APPENDIX 3.  
 
The number and percentage of subjects with at least one TEAE of special interest will be 
presented. The number of events of special interest will also be summarized. 
Listings will be provided for serious adverse events (SAEs), AEs leading to death, AEs leading 
to discontinuation of study drug and AEs of special interest.  
13.3. CLINICAL LABORATORY EVALUATION 
Laboratory evaluations that are done at study site visits will be collected and processed via a 
central laboratory, and presented in standard international (SI) units. Laboratory evaluations 
that are required at intervals that do not coincide with study site visits may be obtained by a 
local laboratory. The local laboratory data will be collected on the local laboratory tests form of 
eCRF. 
Clinical laboratory evaluations include, but not limited to, the following: 
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• Chemistry: 
o 
Albumin 
o 
Alkaline phosphatase 
o 
Alanine aminotransferase 
o 
Amylase 
o 
Aspartate aminotransferase 
o 
Bicarbonate 
o 
Bilirubin (total, direct and indirect) 
o 
Blood urea nitrogen 
o 
Calcium (total) 
o 
Chloride 
o 
Cholesterol 
o 
C-reactive protein 
o 
Creatinine 
o 
Estimated glomerular filtration rate (Schwartz formula) 
o 
Gamma-glutamyl transferase 
o 
Glucose 
o 
Lipase 
o 
Magnesium 
o 
Phosphorus 
o 
Potassium 
o 
Sodium 
o 
Triglycerides 
o 
Uric acid 
• Hematology: 
o 
Hematocrit 
o 
Hemoglobin 
o 
Platelet count 
o 
Red blood cell (RBC) count 
o 
RBC morphology, if needed 
o 
White blood cell count with differential 
• Coagulation: 
o 
Prothrombin time/International normalized ratio 
• Urinalysis: 
o 
Blood 
o 
Glucose 
o 
Leucocytes 
o 
Microscopic analysis 
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o 
pH and osmolality 
o 
Protein 
o 
Specific gravity 
 
The laboratory summaries will be based on central lab results only and be presented for 
scheduled site visits only, i.e., baseline, weeks 1, 2, 4, 6, 8, 10, 12, 15, 18, 21, 24 and 28. In 
addition, laboratory results will also be presented at EOT. 
Quantitative results will be summarized for hematology, serum chemistry, and selected 
urinalysis parameters by scheduled site visit. Both observed values and change from baseline 
will be summarized with descriptive statistics defined in Section 6.1. Quantitative laboratory 
measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or “> X”, i.e. 
above the upper limit of quantification (ULQ), will be converted to X for the purpose of 
quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Markedly abnormal laboratory values are defined in APPENDIX 1. These criteria are based on 
lab normal ranges. The number and percentage of subjects with post-baseline results 
qualifying as markedly abnormal as defined in this table will be summarized by parameter and 
a subject level listing will be presented. 
Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis) by subject, parameter, and date of collection. Laboratory values 
outside of the normal range will be flagged. Local lab test results, categorical test results and 
urine pregnancy results will be presented in appendix data listings only. 
13.4. VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
• Pulse Rate (bpm) 
• Temperature (°C) 
• Weight (kg) 
• Height or length (cm) 
• Head circumference (cm) for subjects ≤ 36 months of age 
The following vital signs parameters will be derived for this study: 
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•
BMI (kg/m2) for children 2-15 years of age
•
Weight for length ratio (kg/cm) for infants 4-<12 months corrected gestational age
•
Height or length for age Z-score
•
Weight for age Z-score
•
BMI for age Z-score for children 2-15 years of age
•
Weight for length Z-score for infants 4-<12 months corrected gestational age
• Head circumference for age Z-score for subjects ≤ 36 months of age
Descriptive statistics (e.g., mean, standard deviation, median, minimum and maximum values, 
the number and percent of subjects in specified categories) will be used to summarize the vital 
signs at each scheduled study site visit and at EOT. Both observed value and change from 
baseline will be summarized with descriptive statistics defined in Section 6.1. Mean ± SE plots 
of body weight, height or length, BMI and head circumference for age Z-scores and weight for 
length Z-score by visit will be generated. 
The following specific derivations will be used: 
•
BMI
BMI = 10000* Body weight (kg)/body height (cm)2, where both body weight and body height 
data are available at the same scheduled visit. BMI will only be presented for Children 2-15 
years of age. 
•
Weight for length ratio
Weight for length ratio = Body weight (kg)/length (cm), where both body weight and length 
data are available at the same scheduled visit. Weight for length ratio will only be presented 
for the infant cohort. 
•
Height or length, Weight, Head Circumference, BMI for age Z-scores and weight for length Z-
score
A z-score is the deviation of the value for an individual from the mean value of the reference 
population divided by the standard deviation for the reference population. 
Z-scores are calculated using the formula below: 
Z-score= [((observed value / M) ^ L) – 1] / (S * L), for L≠0 
Z-score= ln(observed value / M) / S, for L=0 
In which ‘observed value’ is the child’s height or length, weight, head circumference or derived 
BMI. The L, M, and S values vary according to the child’s sex, age or length. The following 
data tables containing the L, M and S values for child’s height or length, weight, head 
circumference, derived BMI for age and weight for length will be used.  
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Age 
Height or Length 
Weight 
BMI [3] 
Weight 
for 
Length 
[4] 
Head Circumference 
Children 
1-15 yrs 
[1] 
Infants 
4-<12 
mos [2] 
Children 
1-15 yrs 
[1] 
Infants 
4-<12 
mos [2] 
Children 
1-15 yrs 
[1] 
Infants 
4-<12 
mos [2] 
Children 
1-15 yrs 
[1] 
Infants 
4-<12 
mos [2] 
0-
<12 
mos 
NA 
WHO 
NA 
WHO 
NA 
WHO 
NA 
Kato 
2014 
1-<2 
yrs 
Isojima 
2016 
WHO 
Isojima 
2016 
WHO 
NA 
WHO 
Kato 
2014 
Kato 
2014 
2-3 
yrs 
Isojima 
2016 
NA 
Isojima 
2016 
NA 
Kato 
2011 
NA 
Kato 
2014 
NA 
>3 
yrs 
Isojima 
2016 
NA 
Isojima 
2016 
NA 
Kato 
2011 
NA 
NA 
NA 
[1] Actual (chronological) age at the time of assessment is used for Z-score calculation. 
[2] Corrected gestational age at the time of assessment is used for Z-score calculation. 
[3] BMI is only calculated for Children 2-15 years of age. 
[4] Weight for length is only calculated for the cohort of infants. 
NA = Not applicable; mos = Months; yrs = Years 
To obtain the L, M, and S values using these data tables, the corrected gestational age will be 
used for infants and the actual (chronological) age for children 1-15 years of age. Note that the 
calculated age at each vital sign assessment date will be obtained using the date of birth as 
reference date for actual (chronological) age and (date of birth + difference in days between 
corrected gestational age and actual age at informed consent) as reference date for corrected 
gestational age.   
Details of the Z-score calculation are provided in subsections below. 
Z-scores will be rounded to 2 decimal places for reporting. 
For more information on the LMS method, see 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27365/. 
Official and validated SAS programs created by Centers for Disease Control and Prevention 
(CDC) will be used to calculate the Z-scores for a child’s sex and age (up to 20 years of age) 
for BMI, weight, height, and head circumference based on the L, M, S values referred above. 
For 
more 
information 
on 
the 
CDC 
SAS 
programs, 
see 
http://www.cdc.gov/growthcharts/computer_programs.htm. 
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13.4.1. 
Z-SCORES OF HEIGHT FOR AGE AND WEIGHT FOR AGE FOR CHILDREN 1-15 YEARS OF AGE 
The L, M and S values of height and weight for age for Japanese children as given in Isojima 
et al. (2016) will be used. These values are also given in Table 1 (for height) and Table 2 (for 
weight) of APPENDIX 2. 
For ages (in years) that fall between two age categories given in Table 1 and Table 2, the 
following interpolation will be used to calculate the L, M, S values: 
LMS value=LMS_lower + [(actual age in years – age_lower) * (LMS_upper – LMS_lower)] / 
(age_upper – age_lower). 
Where LMS_lower is the L, M or S value corresponding to the lower age category in the age 
interval, i.e., age_lower, and LMS_upper is the L, M or S value corresponding to the upper age 
category in the age interval, i.e., age_upper. 
For example, according to Table 1 in APPENDIX 2, the M values of height are 135.9 for a 10 
years old male and 138.8 for a 10.5 years old male. Therefore, to obtain the M value of height 
for a 10.2 years old male, the following calculation is applied: 
M=135.9 + [(10.2 – 10) * (138.8 – 135.9)] / (10.5 – 10) = 137.06 
13.4.2. 
Z-SCORES OF LENGTH FOR AGE AND WEIGHT FOR AGE FOR INFANTS 4-12 MONTHS CORRECTED
GESTATIONAL AGE 
L, M, S values for WHO growth charts will be used: 
https://www.cdc.gov/growthcharts/who_charts.htm 
13.4.3. 
Z-SCORES OF HEAD CIRCUMFERENCE FOR ALL STUDY SUBJECTS ≤36 MONTHS OF AGE 
The L, M and S values of head circumference for age for Japanese population as given in 
Kato et al. (2014) will be used. These values are also given in Table 5 of APPENDIX 2. 
Corrected gestational age will be used for infants and the actual (chronological) age for 
children 1-3 years of age. 
For ages (in months) that fall between two age categories given in Table 5, a similar 
interpolation as described in Section 13.4.1 will be used to calculate the L, M, S values. 
13.4.4. 
Z-SCORES OF BMI FOR CHILDREN 2-15 YEARS OF AGE 
The L, M and S values of BMI for age for Japanese children as given in Kato et al. (2011) will 
be used. These values are also given in Table 3 (for male) and Table 4 (for female) of 
APPENDIX 2. BMI for age Z-scores will only be presented for the children 2-15 years of age. 
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13.4.5. 
Z-SCORES OF WEIGHT FOR LENGTH FOR INFANTS 
L, M, S values for WHO growth charts will be used: 
https://www.cdc.gov/growthcharts/who_charts.htm 
Weight for length Z-scores will only be presented for the infant cohort. 
13.5. ECG VARIABLES 
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 12, 
24 and 28 as well as at EOT for the Safety population. 
13.6. PHYSICAL EXAMINATION 
Physical exam findings will be presented in the listings for the Safety population. 
13.7. ANTIBODIES TO TEDUGLUTIDE 
A summary table will provide the number of subjects with a sample analyzed for baseline, 
Week 24, EOT and Week 28. The summary table will also provide the number of subjects with 
an antibody finding (Antibodies to teduglutide Negative/Positive and No Neutralizing 
Antibodies Present/Neutralizing Antibodies Present) at each of those visits. 
13.8. GASTROINTESTINAL-SPECIFIC TESTING 
The results of GI-specific testing including UGI/SBFT, abdominal ultrasound, fecal occult blood 
testing, and colonoscopy/ sigmoidoscopy will be reported as ‘Normal’, ‘Abnormal, not clinically 
significant’, ‘Abnormal, clinically significant’ or ‘Negative’, ‘Positive, not clinically significant’, 
‘Positive, clinically significant’. For the infant cohort, only UGI/SBFT is to be reported. The 
number of patients and percentage will be presented by visit for each GI-specific testing 
parameter and result category. 
13.9. FECAL AND URINE OUTPUT 
Output diary data is recorded over a 48 hour period of PN/IV and EN stability before every 
scheduled site visit and within 1 week of implementing any PN/IV prescription adjustment. For 
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the analysis, the latest 48-hour period of output diary data entered prior to each visit will be 
used (The 48-hour period does not need to be within 48 hours of the visit). Any additional 
output diary data collected out of this 48-hour window will only be presented in the listings. 
The average daily urine output (mL/kg/day) at the scheduled site visit will be calculated as 
follows: 
(Total urine output over 48 hours / 2) / most recent body weight (kg) prior to or on the 
scheduled visit 
where total urine output is calculated as the sum of the urine output in mL and the urine-only 
diaper weights in g (1g = 1mL) for the subject collected on the output diary form of eCRF over 
48 hours. Values will not be calculated if the urine output is not available at the visit.    
The average daily fecal output will be summarized separately by the number of stools per day, 
the typical stool form score using Bristol Stool Form Scale, the total daily stool/mixed stool 
diaper weight (g/kg/day) and the total ostomy output per day (mL/kg/day). The number of 
stools per day and the average typical stool form score will be calculated as (sum of the daily 
data in a 48-hour period / 2). The body weight will be used to calculate the daily stool/mixed 
stool diaper weight (g/kg/day) and the total ostomy output per day (mL/kg/day) using a formula 
analogous to that used to calculate the average daily urine output. 
The change and the percent change in average daily output for urine and fecal from baseline 
to each scheduled visit, as well as at EOT, will be presented using descriptive statistics 
defined in Section 6.1. 
13.10. 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded to indication-specific preferred name using 
the World Health Organization Drug Dictionary. Investigator verbatim as well as coded terms 
will be included in the listings. 
Prior medications are defined as any medication discontinued prior to the administration of 
study treatment. Concomitant medications are defined as any medication taken during the 
course of the study including 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 6.3. 
Prior and concomitant medication use will be summarized by preferred name using the 
number and percentage of subjects. Medications will be sorted alphabetically by preferred 
name. Subjects with multiple occurrences of a medication in preferred name will only be 
counted once within each preferred name. 
A listing of all medications, both prior and concomitant, will be presented. The listing will be 
sorted by subject identifier and will include reported name, dose, route of administration, 
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dosing frequency, start date, end date, indication, and period of medication (prior or 
concomitant). 
14. CHANGES IN THE STATISTICAL METHODOLOGY PRESENTED IN THE PROTOCOL 
There is no change of analysis from protocol. 
15. GENERAL PROGRAMMING INFORMATION 
15.1. GENERAL 
All programmed table, figure and listing outputs, unless specified otherwise, will be generated 
using the SAS version 9.4 or later. The programmed outputs will be similar to the 
format/appearance of the table and listing shells. However, space/formatting limitations may 
dictate changes in the programmed output. The footnotes specified in the table and listing 
shells may be changed as necessary for clarifying table entries or the explanation of 
algorithms or methods used for producing the entries. Significant changes in footnotes will be 
discussed prior to their implementation. 
15.2. FORMAT OF TABLES/LISTINGS 
Tables will present subject cohorts, including all subjects and subset of subjects who began 
treatment after protocol amendment 3.0, in the following order: “Children (1 - 15 years) After 
Amendment 3”, “Total Children (1 - 15 years)”, “Infants (4 - <12 months)”, unless otherwise 
specified. Note that all subjects in the infant cohort will be enrolled after protocol amendment 
3.0 and thus the subset of subjects who began treatment after protocol amendment 3.0 will not 
be presented for the infant cohort. The following footnote will be presented in all tables/listings: 
"Infants are of 4 - <12 months corrected gestational age”. 
All output should have a 1-line footer with the SAS program name, including the path, and the 
date and time the output was produced at the lower left margin of the footer. 
Tables and listings should be internally paginated in relation to the total length for that table or 
listing (i.e., Page n of N, where n is the page number within the table or listing and N is the 
total number of pages for that table or listing). 
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines. 
A number should identify each table/listing, and the table designation (e.g., Table 1) should be 
centered above the title. A decimal system (e.g., x, x.y, x.y.z) should be used to identify 
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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, WHO-DRUG) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary. 
For summarizations of categorical data, an Unknown or Missing category should be added to 
any variable for which information is not available for all subjects. The default denominator will 
be all subjects in the analysis set unless otherwise specified in the SAP. For both tables and 
listings where there are no observations (and hence there would be no output), the table/listing 
should be produced with all titles and footnotes as per its shell, but with the text showing no 
observations in the body of the output. 
Individual data listings will be sorted and presented by cohort, subject number, parameter (if 
applicable) and visit/collection date. 
15.3. DATA FORMATS 
Unless otherwise specified, means (arithmetic, geometric and 95% CI of the mean) and 
medians will be rounded and presented to 1 decimal place more than the raw data and 
standard deviations and standard errors to 2 decimal places more than the raw data. Minimum 
and maximum values will be presented to the same number of decimal places as the raw data. 
Coefficient of variation shall always be reported as a percent with 1 decimal. 
Unless otherwise specified, percentages should be presented to one decimal place. Less than 
signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be presented as < 
0.1%, not 0.0%). 
Standard deviations will be calculated when the number of subjects is 2 or more. 
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16. TABLE, FIGURE AND DATA LISTING SHELLS 
16.1. TABLE SHELLS 
See separate file. 
16.2. FIGURE SHELLS 
See separate file. 
16.3. DATA LISTING SHELLS 
See separate file. 
17. REFERENCES 
• Isojima, T., Kato, N., Ito, Y., Kanzaki, S., and Murata, M. (2016). Growth standard charts for 
Japanese children with mean and standard deviation (SD) values based on the year 2000 
national survey. Clin Pediatr Endocrinol 2016; 25(2), 71–76. 
• Kato, N., Takimoto, H., and Sudo, N. (2011). The Cubic Functions for Spline Smoothed L, S 
and M Values for BMI Reference Data of Japanese Children. Clin Pediatr Endocrinol 2011; 
20(2), 47-49. 
• Kato, N., Takimoto, H., Yokoyama, T., Yokoya, S., Tanaka, T., and Tada, H. (2014). Updated 
Japanese growth references for infants and preschool children, based on historical, ethnic 
and environmental characteristics. Acta Paediatrica 2014; 103, e251-e261.  
 
 
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prohibited. 
 MARKEDLY ABNORMAL LABORATORY CRITERIA   
APPENDIX 1.
 
Lab Parameter 
Unit 
Infants (4 - <12 months 
corrected gestational age) 
Children (1 - 15 years) 
Lower 
Limit 
Criteria 
Upper 
Limit 
Criteria 
Lower 
Limit 
Criteria 
Upper Limit Criteria 
Chemistry 
Albumin  
g/L 
<20 
>68 
<20 
>68 
Alkaline 
Phosphatase  
U/L 
 
>5 x ULN 
 
>5 x ULN 
Alanine 
Aminotransferas
e (ALT) 
U/L 
 
>8 x ULN 
 
>8 x ULN 
Aspartate 
Aminotransferas
e (AST) 
U/L 
 
>8 x ULN 
 
>8 x ULN 
Amylase 
U/L 
 
>3 x ULN 
 
>3 x ULN 
Lipase 
U/L 
 
>3 x ULN 
 
>3 x ULN 
Bilirubin Total 
umol/L 
 
>5 x ULN 
 
>3 x ULN 
Direct Bilirubin 
umol/L 
 
>68.4147 
 
>34.208 
Blood 
Urea 
Nitrogen  
mmol/L 
 
>12.495 
 
>12.495 
Calcium  
mmol/L 
<1.5 
>3 
<1.5 
>3 
Creatinine 
umol/L 
 
>132.6 
 
>132.6 if age < 10 y; 
>150.28 if age 10-
<13 y; 
>176.8 if age 13-<16 
y; 
>221 if age 16+ 
C 
Reactive 
Protein  
mg/L 
 
>=100 
 
>=100 
Glucose 
mmol/L 
<2.22 
>13.875 
<2.22 
>13.875 
Magnesium  
mmol/L 
<0.4114 
>1.2342 
<0.4114 
>1.2342 
Phosphorus  
mmol/L 
<0.644 
>2.254 
<0.644 
>2.254 
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Potassium  
mmol/L 
<2.5 
>6.5 
<2.5 
>6.5 
Sodium  
mmol/L 
<120 
>160 
<120 
>160 
Triglycerides  
mmol/L 
 
>5.65 
 
>5.65 
Hematology 
Hemoglobin  
g/L 
<70 
>200 
<70 
>200 
Hematocrit  
fraction 
of 1 
<0.21 
>0.60 
<0.21 
>0.60 
Platelets  
10^9/L 
<75 
>700 
<75 
>700 
Leukocytes  
10^9/L 
<2 
>30 
<2 
>30 
Neutrophils, 
absolute 
10^9/L 
<0.5 
 
<0.5 
 
 
 
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prohibited. 
 L, M AND S VALUES OF HEIGHT, BODY WEIGHT, 
APPENDIX 2.
BMI AND HEAD CIRCUMFERENCE FOR AGE FOR JAPANESE  
Table 1  
L, M and S Values of Height for Age for Japanese Children 
 
 
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Table 2  
L, M and S Values of Weight for Age for Japanese Children  
 
 
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Table 3  
L, M and S Values of BMI for Age for Japanese Children (Male) 
 
 
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Table 4  
L, M and S Values of BMI for Age for Japanese Children (Female) 
 
 
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Table 5  
L, M and S Values of Head Circumference for Age for Japanese Population 
 
 
 
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 MEDDRA TERMS CORRESPONDING TO EACH 
APPENDIX 3.
GROUPING OF ADVERSE EVENTS OF SPECIAL INTEREST   
 Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGT) 
Tumor-promoting 
ability 
Neoplasms benign, 
malignant and 
unspecified 
  
 
Growth of pre-
existing polyps of 
the colon  
 
 
 
  
Duodenal polyp 
 
  
Intestinal polyp 
 
  
Rectal Polyp 
 
  
Large intestine polyp 
 
  
Gastrointestinal polyp 
 
Benign neoplasia 
of the GI tract 
including the 
hepatobiliary 
system  
  
 
Gastrointestinal 
neoplasms benign 
  
 
Hepatic and biliary 
neoplasms benign 
 
Abdominal wall cyst 
 
 
Abdominal wall neoplasm 
benign 
 
 
Benign abdominal 
neoplasm 
 
 
Benign gastrointestinal 
neoplasm 
 
 
Benign mesenteric 
neoplasm 
 
 
Benign pancreatic 
neoplasm 
 
 
Benign peritoneal 
neoplasm 
 
 
Benign small intestinal 
neoplasm 
 
 
Gastric haemangioma 
 
 
Gastrointestinal polyp 
 
 
Gastrointestinal polyp 
haemorrhage 
 
 
Gastrointestinal tract 
adenoma 
 
 
Gingival cyst 
 
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 Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGT) 
 
Intestinal angioma 
 
 
Intestinal cyst 
 
 
Intestinal polyp 
 
 
Intra-abdominal 
haemangioma 
 
 
Intraductal papillary 
mucinous neoplasm 
 
 
Large intestine benign 
neoplasm 
 
 
Mesenteric cyst 
 
 
Pancreatic cyst 
 
 
Pancreatic cyst rupture 
 
 
Peutz-Jeghers syndrome 
 
 
Retroperitoneum cyst 
 
 
Small intestine polyp 
 
 
Stoma site polyp 
 
 
Adenolymphoma 
 
 
Ameloblastoma 
 
 
Benign keratocystic 
odontogenic neoplasm 
 
 
Benign salivary gland 
neoplasm 
 
 
Buccal polyp 
 
 
Cementoblastoma 
 
 
Dental cyst 
 
 
Gingival polyp 
 
 
Lip neoplasm benign 
 
 
Mouth cyst 
 
 
Odontogenic cyst 
 
 
Oral fibroma 
 
 
Oral haemangioma 
 
 
Oral neoplasm benign 
 
 
Oral papilloma 
 
 
Papillary cystadenoma 
lymphomatosum 
 
 
Pleomorphic adenoma 
 
For non-commercial use only


 
Statistical Analysis Plan 
 
PROTOCOL SHP633-302 
Page 44 of 45 
 
Document: 
T:\Shire\Teduglutide\XXA39799\Biostatistics\Documentation\SAP\SHP633-302_SAP_Final 
1.0_17Apr2019.docx 
Author: 
Version Number: 
Final 1.0 
 
 
Version Date: 
17Apr2019 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © IQVIA. All rights reserved. 
The contents of this document are confidential and proprietary to IQVIA. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
 Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGT) 
 
Salivary gland adenoma 
 
 
Salivary gland cyst 
 
 
Tongue cyst 
 
 
Tongue neoplasm benign 
 
 
Tongue polyp 
 
 
White sponge naevus 
 
 
Anal polyp 
 
 
Appendix adenoma 
 
 
Benign anorectal 
neoplasm 
 
 
Colon adenoma 
 
 
Large intestine fibroma 
 
 
Large intestine polyp 
 
 
Rectal adenoma 
 
 
Rectal polyp 
 
 
Benign duodenal 
neoplasm 
 
 
Benign gastric neoplasm 
 
 
Benign oesophageal 
neoplasm 
 
 
Duodenal polyp 
 
 
Gastric adenoma 
 
 
Gastric cyst 
 
 
Gastric polyps 
 
 
Oesophageal cyst 
 
 
Oesophageal papilloma 
 
 
Oesophageal polyp 
 
 
Biliary cyst 
 
 
Biliary polyp 
 
 
Choledochal cyst 
 
 
Congenital cystic disease 
of liver 
 
 
Gallbladder polyp 
 
 
Haemorrhagic hepatic cyst  
 
Hepatic cyst 
 
For non-commercial use only


 
Statistical Analysis Plan 
 
PROTOCOL SHP633-302 
Page 45 of 45 
 
Document: 
T:\Shire\Teduglutide\XXA39799\Biostatistics\Documentation\SAP\SHP633-302_SAP_Final 
1.0_17Apr2019.docx 
Author: 
Version Number: 
Final 1.0 
 
 
Version Date: 
17Apr2019 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © IQVIA. All rights reserved. 
The contents of this document are confidential and proprietary to IQVIA. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
 Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGT) 
 
Hepatic cyst infection 
 
 
Hepatic cyst ruptured 
 
 
Benign biliary neoplasm 
 
 
Benign hepatic neoplasm 
 
 
Benign hepatobiliary 
neoplasm 
 
 
Benign neoplasm of 
ampulla of Vater 
 
 
Biliary adenoma 
 
 
Biliary hamartoma 
 
 
Cholangioadenoma 
 
 
Focal nodular hyperplasia 
 
 
Gallbladder adenoma 
 
 
Gallbladder papilloma 
 
 
Haemangioma of liver 
 
 
Hepatic adenoma 
 
 
Hepatic haemangioma 
rupture 
 
Note: MedDRA terms are based on MedDRA version 20.0. 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
1 
13-Sep-2019 
  
 
TITLE PAGE 
PK ANALYSIS PLAN 
 
A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of 
Teduglutide in Japanese Pediatric Subjects, Aged 4 Months through 15 Years, with 
Short Bowel Syndrome who are Dependent on Parenteral Support 
 
 
Sponsor Protocol No.: SHP633-302 (Amendment 4: 12-Jun-2018) 
Investigational Product: SHP633 (Teduglutide) 
 
Final 
Date: 13-Sep-2019 
 
CSC Reference No.: SHIR-PCS-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. 
 
 
For non-commercial use only


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For non-commercial use only


PK Analysis Plan 
Japanese Pediatric 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 Concentrations of Teduglutide .............................................................................................8 
7.2.1 Handling of Incomplete and/or Non-Compliant Data ...................................................8 
7.2.2 Unexpected Data ............................................................................................................8 
7.3 Summarization of Teduglutide Concentrations ...................................................................8 
7.4 Software ...............................................................................................................................9 
7.5 Quality Control and Quality Assurance ...............................................................................9 
8 
ARCHIVING...........................................................................................................................9 
9 
APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS.....................................10 
10 APPENDIX 2: TABLE AND FIGURE SHELLS ..............................................................12 
 
 
 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 4 
13-Sep-2019 
2 
LIST OF ABBREVIATIONS 
Term 
Definition 
BLQ 
Below limit of quantification 
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 
Max 
Maximum 
Mean 
Arithmetic mean 
Min 
Minimum 
N 
Sample size 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetics(s) 
PN 
Parenteral Support 
SBS 
Short bowel syndrome 
SC 
Subcutaneous 
SD 
Standard deviation 
sFTP 
Secure File Transfer Protocol 
SOP 
Standard operating procedures 
 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric 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 SHP633-302 
(Amendment 4, dated 12-Jun-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 multiple-dose PK of teduglutide 0.05 mg/kg administered 
subcutaneously in Japanese pediatric subjects, aged 4 months through 15 years, with short bowel 
syndrome who are dependent on parenteral 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 concentrations of teduglutide after single 
and repeated subcutaneous (SC) administration of teduglutide 0.05 mg/kg in Japanese pediatric 
subjects, aged 4 months through 15 years with short bowel syndrome who are dependent on 
parenteral support. PK parameters will not be derived due to the sparse data collected (ie, only 2 
concentrations post-dose).    
A population PK analysis will be performed after combining multiple studies.  The data collected 
in the current study will be included in the population PK analysis.  Details on the population PK 
analysis are covered in a separate analysis plan. 
 
5 
STUDY DESIGN 
Protocol SHP633-302 was a 24-week safety, efficacy, pharmacodynamic, and PK study of 
teduglutide in Japanese pediatric subjects, aged 4 months through 15 years, with short bowel 
syndrome (SBS) who are dependent on parenteral support.  Planned enrollment is a minimum of 
5 subjects aged 1 through 15 years and a minimum of 2 subjects of 4 to <12 months corrected for 
gestational age.  
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric 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) 
 
EOS=end of study; EOT=end of treatment 
During the treatment period, a SC dose of 0.05 mg/kg/day of teduglutide was administered once 
daily to the subjects for 24 weeks. The dose calculation was based on body weight measured at the 
baseline visit (visit 2) and may be adjusted at Week 12 (visit 14).  
Subjects participated in a minimum 2-week screening period from the time of the screening visit 
to the baseline visit, followed by 24 weeks of treatment. Attempts were made to limit the screening 
period to 4 weeks. The EOS visit was scheduled at Week 28, 4 weeks after the EOT visit 
(Week 24).  
Following reconstitution, teduglutide was administered by SC injection once daily into 1 of the 4 
quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For subjects 
with a stoma, the quadrant of the abdomen containing the stoma was not used. Each day, the 
injection site was to be rotated. The site of administration (arm, thigh, or abdomen) of the first 
teduglutide dose was specified and recorded in the eCRF. 
Blood samples for teduglutide concentrations were collected at the baseline and at the Week 4 
visits as presented in Table 1.  
Table 1.  
Blood Sample Collection Schedule for Pharmacokinetic Testing 
Study week 
Baseline 
Week 4 
Visit Number 
2 
6 
Hour 
0a 
1 
6 
0a 
2 
4 
a Prior to investigational product administration 
Some deviations from the above timepoints may have occurred. The investigator or designee kept 
deviations to a minimum and guided by the following collection windows: 
• 0-h (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 14 h 
after the previous dose (at the week 4 draw). 
• 1-h postdose draw: ±10 min 
• 2-h postdose draw: ±10 min 
• 4-h postdose draw: ±30 min 
• 6-h postdose draw: ±30 min 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
CSC Confidential 
Page 7 
13-Sep-2019 
If a blood sample was not collected at Week 4, the uncollected sample could be collected during 
any future site visit while the subject is still receiving the investigational product. In smaller 
children for whom blood sampling may impose unacceptable phlebotomy volume, the number of 
PK samples may have been reduced. 
At PK timepoints, the date and time of investigational product administration and blood collection 
must be recorded on the eCRF. 
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 data. 
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. Electronic Data Transmission (EDT) contact at Takeda will be: 
, 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 will be 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. 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 8 
13-Sep-2019 
7.2 
Concentrations of Teduglutide 
7.2.1 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. 
7.2.2 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. 
7.3 
Summarization of Teduglutide Concentrations  
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. 
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  
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 9 
13-Sep-2019 
• 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 at Visit 2 and 6.  Results will be presented overall, and by age groups 
(4 to <12 months and 1 to 15 years).  
No PK parameters will be derived considering the sparse data collected at Visit 2 and 6 (ie, only 2 
samples after dosing are available).   
7.4 
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.  
7.5 
Quality Control and Quality Assurance 
Data sets, table and figures will be quality-controlled by two scientists at CSC (ie, by the originator 
of the work and by a reviewer) as per CSC SOP-104 entitled, “Managing Data in CSC” and CSC 
SOP-114 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. 
 
 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 10 
13-Sep-2019 
9 
APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS 
14. 
PHARMACOKINETIC TABLES AND FIGURES 
 
14.1. Plasma Teduglutide Concentration-Time Tables by Visit  
Table 14.2.1. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Baseline (Visit 2) 
Table 14.2.2. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Visit 4 (Week 6) 
 
Table 14.2.3. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Baseline (Visit 2) - Unscheduled Visit (if applicable) 
Table 14.2.4. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Visit 4 (Week 6) - Unscheduled Visit (if applicable) 
 
14.2. Plasma Teduglutide Concentration-Time Tables by Visit and Age  
Table 14.2.5. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Baseline (Visit 2, 4 to <12 months) 
Table 14.2.6. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Baseline (Visit 2, 1 to 15 years) 
 
Table 14.2.7. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Visit 4 (Week 6, 4 to <12 months) 
Table 14.2.8. Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Visit 4 (Week 6, 1 to 15 years) 
 
 
 
 
 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 11 
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) 
  
 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 12 
13-Sep-2019 
10 APPENDIX 2: TABLE AND FIGURE SHELLS 
Concentration-Time Profiles 
Figure 14.1.1 Mean (+SD) Plasma Teduglutide Concentrations vs. Time after SC 
Administration of Teduglutide by Treatment – Baseline (Visit 2) (Linear and 
Semi-Log) 
 
  
 
Semi-Log Plot 
 
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly (ie, 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) 
For non-commercial use only


PK Analysis Plan 
Japanese Pediatric Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 13 
13-Sep-2019 
Individual and Summary Concentration-Time Tables 
Table 14.2.1 Plasma Teduglutide Concentrations vs. Time after a SC Administration of 
Teduglutide 0.05 mg/kg – Baseline (Visit 2) 
Subject ID 
Plasma Teduglutide Concentrations (Unit) over Nominal Time (h) 
 
0.0 
1.0 
6.0 
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 at Visit 4  
For non-commercial use only