A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age With Short Bowel Syndrome Who Are Dependent on Parenteral Support
Phase: PHASE3
Conditions: Short Bowel Syndrome
Sponsor: Shire

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

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

PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD P 
, Global C m1cal Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Date: 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) ofthis study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to tllis protocol and to comply with its requirements, 
subject to etllical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Hun1an Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: -------------------------------- Date: 
Shire 
CONFIDENTIAL 
Page 2 
SHP633-301 Protocol 
 
Teduglutide 
 
03 Oct 2017 
 
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol
Teduglutide
03 Oct 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact Quintiles Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email: 
Email: 
In addition, the investigator may also contact Shire:
, PharmD, MSc
Phone: 
Mobile: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol
Teduglutide
03 Oct 2017
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol
Teduglutide
03 Oct 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................10
STUDY SYNOPSIS ......................................................................................................................11
STUDY SCHEDULES ..................................................................................................................16
BACKGROUND INFORMATION .......................................................................................20
1.
1.1
Short Bowel Syndrome ............................................................................................20
1.2
Teduglutide...............................................................................................................21
OBJECTIVES.........................................................................................................................22
2.
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
STUDY DESIGN ...................................................................................................................23
3.
3.1
Study Design and Flow Chart ..................................................................................23
3.1.1
Screening Period ....................................................................................................23
3.1.2
Treatment Period....................................................................................................23
3.1.3
Follow-up Period ...................................................................................................24
3.2
Study Duration .........................................................................................................24
3.3
Sites and Regions .....................................................................................................24
STUDY POPULATION.........................................................................................................25
4.
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................25
4.3
Reproductive Potential .............................................................................................26
4.4
Discontinuation of Subjects .....................................................................................26
4.4.1
Reasons for Discontinuation..................................................................................27
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................27
PRIOR AND CONCOMITANT TREATMENT ...................................................................28
5.
5.1
Prior Medications and Procedures............................................................................28
5.2
Concomitant Medications and Procedures...............................................................28
5.3
Permitted Treatment.................................................................................................28
5.4
Prohibited Treatment................................................................................................28
INVESTIGATIONAL PRODUCT ........................................................................................29
6.
6.1
Identity of Investigational Product...........................................................................29
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol
Teduglutide
03 Oct 2017
6.2
Administration of Investigational Product ...............................................................29
6.2.1
Interactive Response Technology for Investigational Product Management ........29
6.2.2
Allocation of Subjects to Treatment ......................................................................29
6.2.3
Dosing....................................................................................................................29
6.2.4
Unblinding the Treatment Assignment..................................................................30
6.2.5
Dose Selection Rationale .......................................................................................30
6.3
Labeling, Packaging, and Storage ............................................................................31
6.3.1
Labeling .................................................................................................................31
6.3.2
Storage and Handling.............................................................................................31
6.4
Drug Accountability.................................................................................................32
6.5
Subject Compliance..................................................................................................33
STUDY PROCEDURES........................................................................................................34
7.
7.1
Study Schedule.........................................................................................................34
7.1.1
Screening................................................................................................................34
7.1.2
Treatment Period....................................................................................................34
7.1.3
Follow-up Period ...................................................................................................34
7.2
Study Evaluations and Procedures ...........................................................................34
7.2.1
Demographics and Other Baseline Characteristics................................................34
7.2.2
Efficacy Assessments.............................................................................................35
7.2.3
Safety Assessments................................................................................................36
7.2.4
Pharmacokinetic Assessments ...............................................................................39
7.2.5
Health Economics and Outcomes Research ..........................................................39
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................41
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................41
8.1.1
Severity Categorization..........................................................................................41
8.1.2
Relationship Categorization...................................................................................42
8.1.3
Outcome Categorization ........................................................................................42
8.1.4
Symptoms of the Disease under Study ..................................................................43
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................43
8.1.6
Pregnancy...............................................................................................................43
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................43
8.2
Serious Adverse Event Procedures ..........................................................................44
8.2.1
Reference Safety Information ................................................................................44
8.2.2
Reporting Procedures.............................................................................................44
8.2.3
Serious Adverse Event Definition .........................................................................45
8.2.4
Serious Adverse Event Collection Time Frame.....................................................45
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................45
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol
Teduglutide
03 Oct 2017
8.2.6
Fatal Outcome........................................................................................................46
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................46
8.3
Adverse Events of Special Interest...........................................................................46
8.4
Dose Interruption Criteria ........................................................................................47
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................48
9.
9.1
Data Collection.........................................................................................................48
9.2
Clinical Data Management.......................................................................................48
9.3
Statistical Analysis Process......................................................................................48
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................48
9.5
Sample Size Calculation and Power Considerations................................................49
9.6
Study Population ......................................................................................................49
9.7
Efficacy Analyses.....................................................................................................49
9.8
Safety Analyses ........................................................................................................51
9.9
Health Economics and Outcomes Research Analyses .............................................51
9.10
Pharmacokinetics Analyses......................................................................................52
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................53
10.
10.1
Sponsor’s Responsibilities .......................................................................................53
10.1.1 Good Clinical Practice Compliance.......................................................................53
10.1.2 Indemnity/Liability and Insurance.........................................................................53
10.1.3 Public Posting of Study Information......................................................................53
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................54
10.1.5 Study Suspension, Termination, and Completion..................................................54
10.2
Investigator’s Responsibilities .................................................................................54
10.2.1 Good Clinical Practice Compliance.......................................................................54
10.2.2 Protocol Adherence and Investigator Agreement ..................................................55
10.2.2.1
Documentation and Retention of Records .............................................55
10.2.2.2
Electronic Case Report Forms................................................................55
10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................55
10.2.2.4
Audit/Inspection .....................................................................................56
10.2.2.5
Financial Disclosure...............................................................................56
10.3
Ethical Considerations..............................................................................................56
10.3.1 Informed Consent...................................................................................................56
10.3.2 Institutional Review Board or Ethics Committee ..................................................57
10.4
Privacy and Confidentiality......................................................................................57
10.5
Study Results/Publication Policy .............................................................................58
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol
Teduglutide
03 Oct 2017
REFERENCES .......................................................................................................................60
11.
APPENDICES ........................................................................................................................62
12.
Appendix 1
Protocol History .....................................................................................63
Appendix 2
Guidelines for Nutritional Support Management During the Study ......64
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol
Teduglutide
03 Oct 2017
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................16
Table 2:
Study Schedule: Visits 13-28 ........................................................................18
Table 3:
Prohibited Treatment.....................................................................................28
Table 4:
List of Laboratory Tests ................................................................................37
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................38
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................23
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol
Teduglutide
03 Oct 2017
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCtau,ss
area under the concentration-time curve at steady-state over the dosing interval
CL/F
apparent clearance
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EQ-5D-5L
5-level EuroQol five dimensions questionnaire
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol
Teduglutide
03 Oct 2017
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a minimum 2-week 
screening period, a 24-week treatment period, and a 4-week follow-up period. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks).  At the 
baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization 
will be stratified according to the presence of a small bowel ostomy (end jejunostomy or ileostomy).  During the 
24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.  
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (t=0, 1, and 4 hours) and at 
Week 6 or 12 (t= 2 hours) .
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS the subject may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period may be 
interrupted and the subject may consent to the extension study immediately if at least one of the following 
“escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2-week screening period, a 24- week treatment period, and a 4-week follow-up period.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized parenteral nutrition (PN) fluid volume by at least 20% from baseline at 
Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
Pharmacokinetic endpoints include but are not limited to the following:

Area under the plasma concentration–time curve at steady state over the dosing internal (AUCtau, ss)

Maximum plasma concentration at steady state (Cmax,ss)

Apparent clearance (CL/F)
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

The 5-level EuroQol five dimensions questionnaire (EQ5D-5L) quality of life questionnaire to be 
completed by the subjects’ caregivers at baseline and Week 24

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period.  During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and there is no use of PN 
recorded in the subject diary during the week prior to that visit. The number and percentage of subjects who 
achieve enteral autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, and standard deviation) at 
nominal time points. Pharmacokinetic parameters will be derived using a population PK modeling approach and 
summarized using descriptive statistics (number, mean, standard deviation, geometric mean, coefficient of 
variation, minimum, median, and maximum). 
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol
Teduglutide
03 Oct 2017
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
X
(X)
X
(X)
X
(X)
(X)
X
(X)
(X)
X
PK samplinga
X
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
EN=enteral nutrition;EQ-5D-5L=five-level EuroQol five dimensions questionnaire; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; 
PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with short bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 and 4 hours post dose at baseline (Visit 0).  Subjects also will have blood samples taken for teduglutide PK analysis 
2 hours post dose at Week 6 (Visit 6) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0), and adjusted as needed, based on body weight measured at each in-clinic study visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X) 
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteria
X
X
X
X
Dispense IPd, i
X
X
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; EQ-5D-5L=five-level EuroQol five dimensions questionnaire; ET=early termination; GLP-2=glucagon-like peptide 2; 
INR=international normalized ratio; IP=investigational product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with short bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i The dose will be adjusted as needed, based on body weight measured at each in-clinic study visit.
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol
Teduglutide
03 Oct 2017
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN) fluids (O'Keefe 
et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with serious 
complications, including liver disease, life-threatening catheter-related blood stream infections, 
and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  Dependence 
on PN is also associated with reduced quality of life in both patients and caregivers and has an 
extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants with SBS 
become independent of PN requirements within 12 months of the initial insult, and an additional 
10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It is 
estimated that 42% to 86% of pediatric patients with SBS are able to become independent of PN 
within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol
Teduglutide
03 Oct 2017
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol
Teduglutide
03 Oct 2017
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol
Teduglutide
03 Oct 2017
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a minimum 2-week screening 
period, a 24-week treatment period and a 4-week follow-up period. A schematic representation 
of the study design is presented in Figure 1.
Figure 1:
Study Schematic
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum:
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (end 
jejunostomy or ileostomy).  During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard medical 
therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 2, 4, 6, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed.  To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Sparse PK sampling, in the teduglutide treatment arm, will occur at baseline (t=0, 1, and 4 hours) 
and at Week 6 or 12 (t=2 hours).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS the subject 
may enroll in an extension study that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period may be interrupted and 
the subject may consent to the extension study immediately if at least one of the following 
"escape" criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a minimum 2-week screening period, a 24-week treatment period and a 
4-week follow-up period.
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol
Teduglutide
03 Oct 2017
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol
Teduglutide
03 Oct 2017
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol
Teduglutide
03 Oct 2017
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol
Teduglutide
03 Oct 2017
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol
Teduglutide
03 Oct 2017
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 5 mg or 1.25 mg 
teduglutide as a white lyophilized powder to be reconstituted before use with 0.5 mL sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the current investigator’s 
brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  The actual treatment 
given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at each in-clinic study visit.  No other 
adjustments to dose will be made during the teduglutide treatment period, unless discussed with 
the sponsor’s medical monitor.  
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol
Teduglutide
03 Oct 2017
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
Following the 24-week Treatment Period, subjects will enter a 4-week follow-up period. During 
the follow-up, the investigator will assess the subject via weekly telephone visits. The follow-up 
period may be interrupted and the subject may consent to the extension study immediately if at 
least one of the following criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol
Teduglutide
03 Oct 2017
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures.  Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study.  A copy of the shipping documents 
must be maintained for the investigator’s records.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol
Teduglutide
03 Oct 2017
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record. The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol
Teduglutide
03 Oct 2017
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent/assent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent/assent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Short Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol
Teduglutide
03 Oct 2017
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support.  The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be 
collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  The investigator should contact the 
medical monitor within 24 hours of their awareness if the subject develops any of the following 
changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol
Teduglutide
03 Oct 2017
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 
Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6
Baseline: 3 timepoints
Week 6: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
0.1
3
0.3
Total mL:
4.9
36
28.2
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
0.1
3
0.3
Total mL:
1.3
26
14.1
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1, and Table 
2). Any new clinically significant findings noted during physical examinations should be 
recorded on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose and 1 and 4 hours 
post dose at baseline (Visit 0).  Subjects also will have blood samples taken for teduglutide PK 
analysis 2 hours post dose at Week 6 (Visit 6) or Week 12 (Visit 12) of the treatment period.  
Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a central 
line.  The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) must 
be specified.  
7.2.5
Health Economics and Outcomes Research
Five-level EuroQol Five-dimensions Questionnaire
To assess caregiver burden, parents/legally authorized representatives will be asked to complete 
the 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) at the visits specified in Table 1, 
and Table 2. The EQ-5D-5L is a generic, multi-attribute, health related QOL questionnaire 
composed of a descriptive system and a visual analog scale (VAS) (Herdman et al., 2011).
The EQ-5D-5L descriptive system has the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, or extreme problems.  In addition to 
showing which levels the subject selected for the 5 dimensions, the information from the 
5 dimensions can also be combined to provide a value from 0, representing death, to 1, 
representing perfect health.  The VAS provides results from 0, labeled “worst imaginable health 
state” to 100, labeled “best imaginable health state.”  
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol
Teduglutide
03 Oct 2017
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol
Teduglutide
03 Oct 2017
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol
Teduglutide
03 Oct 2017
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol
Teduglutide
03 Oct 2017

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol
Teduglutide
03 Oct 2017
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol
Teduglutide
03 Oct 2017
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol
Teduglutide
03 Oct 2017
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol
Teduglutide
03 Oct 2017
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol
Teduglutide
03 Oct 2017
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: All subjects who have at least one safety assessment after the 
baseline visit.
Per-protocol population: All subjects in the ITT population without a major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects randomized in the teduglutide treatment arm 
for which the primary PK data are sufficient and interpretable.
9.7
Efficacy Analyses
Efficacy endpoints consist of the following:
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol
Teduglutide
03 Oct 2017

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample.  As such, no claims of significance will be made for any of the data.  
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum.  For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period.  During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and there is no use of PN recorded in the subject 
diary during the week prior to that visit. The number and percentage of subjects who achieve 
enteral autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment 
arm.  
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol
Teduglutide
03 Oct 2017
9.8
Safety Analyses
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

EQ5D-5L

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol
Teduglutide
03 Oct 2017
9.10
Pharmacokinetics Analyses
Pharmacokinetic endpoints include but are not limited to the following:

Area under the plasma concentration-time curve at steady-state 
over the dosing interval (AUCtau,ss)

Maximum plasma concentration at steady-state (Cmax,ss)

Apparent clearance (CL/F)
Plasma concentrations will be summarized using descriptive statistics (number, mean, and 
standard deviation) at nominal time points.  Pharmacokinetic parameters will be estimated using 
a population PK modeling approach as appropriate and summarized using descriptive statistics 
(number, mean, standard deviation, geometric mean, coefficient of variation, minimum, median, 
and maximum). 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol
Teduglutide
03 Oct 2017
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol
Teduglutide
03 Oct 2017
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol
Teduglutide
03 Oct 2017
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol
Teduglutide
03 Oct 2017
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from the parent(s)/guardian(s) of all study subjects prior to any study-related 
procedures including screening assessments. All consent and assent documentation must be in 
accordance with applicable regulations and GCP. Each subject’s legally authorized 
representative is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (i.e., a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject’s 
legally authorized representative, as applicable. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol
Teduglutide
03 Oct 2017
This document may require translation into the local language. Signed consent forms must 
remain in each subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent form
where applicable) that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (i.e., sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol
Teduglutide
03 Oct 2017
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol
Teduglutide
03 Oct 2017
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G. & Badia, X. 
2011. Development and preliminary testing of the new five-level version of EQ-5D (EQ-
5D-5L). Quality of Life Research, 20, 1727-1736.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J.
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol
Teduglutide
03 Oct 2017
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol
Teduglutide
03 Oct 2017
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects 
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific 
gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption
For non-commercial use only

1111 
I 
Protocol Administrative Clarification 
MEMORANDUM 
To: 
SHP633-301 Trial Master File (TMF), SHP633-301 Study Sites 
From: 
, MS -
 and 
, MBA -
 
Date: 
08 Nov 2017 
Subject: Protocol Administrative Clarification Memorandum 
EUDRACT NO: 2017-003606-40 
Protocol Title: 
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of Teduglutide in Infants 
4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral Support 
Protocol Version: 
Original Protocol 03 Oct 2017 
The following Administrative Letter is for Protocol SHP633-301, Original Version dated 03 Oct 2017. These changes are considered 
administrative in nature and the clarifications do not compromise the scope, design, or integrity of the study. These changes do not 
compromise subject safety in any way. 
The administrative changes include: 
1. 
To clarify the duration of the screening period and total time on study: The study consists of a screening period of 2-4 
weeks, a 24-week treatment period, and a 4-week follow-up period for a total of up to 30-32 weeks total time on study. 
2. 
To clarify the study schematic: The study schematic will be replaced with the following diagram: 
Screening 
Teduglutide 0.05 mg/kg SC once daily for 24 weeks 
4 
6 
4 
6 
Baseline: treatment 
randomization 
. . . 
9 
12 
16 
20 
-- Site Visit ····Telephone Visit 
Standard of care for 24 weeks 
. . 
. . . 
. 
. . . . . . . 
9 
12 
16 
20 
cc: SHP633-301 TMF Main Study File 
. . 
. . 
. . 
. 
. . 
24 
Extension 
study 
28 
For non-commercial use only

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

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

Shire 
CONFIDENTIAL 
Page2 
SHP633-301 Protocol 
Teduglutide 
18 Jan 2018 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD PhD 
, Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Date: 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, PharmD, MSc
Phone: 
Mobile: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2,
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
Synopsis, Section 4.1
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
gestational age at screening.
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
See Appendix 1 for protocol history, including all amendments.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................13
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULES ..................................................................................................................19
BACKGROUND INFORMATION .......................................................................................23
1.
1.1
Short Bowel Syndrome ............................................................................................23
1.2
Teduglutide...............................................................................................................24
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ..................................................................................26
3.1.1
Screening Period ....................................................................................................26
3.1.2
Treatment Period....................................................................................................26
3.1.3
Follow-up Period ...................................................................................................27
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................28
STUDY POPULATION.........................................................................................................29
4.
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................30
4.4
Discontinuation of Subjects .....................................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................31
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.
5.1
Prior Medications and Procedures............................................................................32
5.2
Concomitant Medications and Procedures...............................................................32
5.3
Permitted Treatment.................................................................................................32
5.4
Prohibited Treatment................................................................................................32
INVESTIGATIONAL PRODUCT ........................................................................................33
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
6.1
Identity of Investigational Product...........................................................................33
6.2
Administration of Investigational Product ...............................................................33
6.2.1
Interactive Response Technology for Investigational Product Management ........33
6.2.2
Allocation of Subjects to Treatment ......................................................................33
6.2.3
Dosing....................................................................................................................33
6.2.4
Unblinding the Treatment Assignment..................................................................34
6.2.5
Dose Selection Rationale .......................................................................................34
6.3
Labeling, Packaging, and Storage ............................................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability.................................................................................................36
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................39
7.
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening................................................................................................................39
7.1.2
Treatment Period....................................................................................................39
7.1.3
Follow-up Period ...................................................................................................39
7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Demographics and Other Baseline Characteristics................................................39
7.2.2
Efficacy Assessments.............................................................................................40
7.2.3
Safety Assessments................................................................................................41
7.2.4
Pharmacokinetic Assessments ...............................................................................44
7.2.5
Health Economics and Outcomes Research ..........................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................47
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest...........................................................................50
8.4
Dose Interruption Criteria ........................................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Statistical Analysis Process......................................................................................52
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................52
9.5
Sample Size Calculation and Power Considerations................................................53
9.6
Study Population ......................................................................................................53
9.7
Efficacy Analyses.....................................................................................................54
9.7.1
Efficacy Endpoints.................................................................................................54
9.7.1.1
Primary Efficacy Endpoint.....................................................................54
9.7.1.2
Secondary Efficacy Endpoints ...............................................................54
9.7.2
Method of Analysis-Efficacy Endpoints................................................................54
9.8
Safety Analyses ........................................................................................................55
9.8.1
Safety Endpoints ....................................................................................................55
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................56
9.10
Pharmacokinetics Analyses......................................................................................56
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................57
10.
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Indemnity/Liability and Insurance.........................................................................57
10.1.3 Public Posting of Study Information......................................................................57
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................58
10.1.5 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement ..................................................59
10.2.2.1
Documentation and Retention of Records .............................................59
10.2.2.2
Electronic Case Report Forms................................................................59
10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
10.2.2.4
Audit/Inspection .....................................................................................60
10.2.2.5
Financial Disclosure...............................................................................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board or Ethics Committee ..................................................61
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................62
REFERENCES .......................................................................................................................64
11.
APPENDICES ........................................................................................................................66
12.
Appendix 1
Protocol History .....................................................................................67
Appendix 2
Guidelines for Nutritional Support Management During the Study ......68
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................19
Table 2:
Study Schedule: Visits 13-28 ........................................................................21
Table 3:
Prohibited Treatment.....................................................................................32
Table 4:
List of Laboratory Tests ................................................................................42
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................43
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will 
capture long-term safety data and provide the opportunity for additional teduglutide treatment.  
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
Exclusion Criteria
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard 
medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening.  Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 1.25 mg teduglutide as a 
white lyophilized powder to be reconstituted before use with 0.5 mL sterile water for injection. 
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients. Additional information is provided in the current investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures.  Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study.  A copy of the shipping documents 
must be maintained for the investigator’s records.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample.  As such, no claims of significance will be made for any of the data.  
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum.  For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
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

Page2 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
ment 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution ofthe study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 
Shire
CONFIDENTIAL
Page 2
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD, PhD 
Phone: 
Mobile: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact 
Information
Added an exclusion criterion for Gilbert’s disease and liver 
failure based on the values of the transaminases and of total 
bilirubin as requested by Agence Nationale de Sécurité du 
Medicament et des Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace 
residues of tetracycline to be consistent with the European 
Summary of Product Characteristics of teduglutide as 
requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and 
discomfort during procedures such as peripheral venipuncture 
will be implemented.
Section 7.2.3
See Appendix 1 for protocol history, including all amendments.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome..................................................................................21
1.2
Teduglutide....................................................................................................22
OBJECTIVES.........................................................................................................................23
2.
2.1
Rationale for the Study..................................................................................23
2.2
Study Objectives............................................................................................23
STUDY DESIGN ...................................................................................................................24
3.
3.1
Study Design and Flow Chart........................................................................24
3.1.1
Screening Period ...............................................................................................24
3.1.2
Treatment Period...............................................................................................24
3.1.3
Follow-up Period...............................................................................................25
3.2
Study Duration...............................................................................................25
3.3
Sites and Regions ..........................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria...........................................................................................27
4.2
Exclusion Criteria..........................................................................................27
4.3
Reproductive Potential ..................................................................................29
4.4
Discontinuation of Subjects...........................................................................29
4.4.1
Reasons for Discontinuation .............................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ............................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures.................................................................31
5.2
Concomitant Medications and Procedures ....................................................31
5.3
Permitted Treatment ......................................................................................31
5.4
Prohibited Treatment.....................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
6.1
Identity of Investigational Product ................................................................32
6.2
Administration of Investigational Product ....................................................32
6.2.1
Interactive Response Technology for Investigational Product 
Management......................................................................................................32
6.2.2
Allocation of Subjects to Treatment .................................................................32
6.2.3
Dosing ...............................................................................................................32
6.2.4
Unblinding the Treatment Assignment .............................................................33
6.2.5
Dose Selection Rationale ..................................................................................33
6.3
Labeling, Packaging, and Storage .................................................................34
6.3.1
Labeling.............................................................................................................34
6.3.2
Storage and Handling........................................................................................34
6.4
Drug Accountability ......................................................................................35
6.5
Subject Compliance.......................................................................................36
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule ..............................................................................................38
7.1.1
Screening...........................................................................................................38
7.1.2
Treatment Period...............................................................................................38
7.1.3
Follow-up Period...............................................................................................38
7.2
Study Evaluations and Procedures ................................................................38
7.2.1
Demographics and Other Baseline Characteristics ...........................................38
7.2.2
Efficacy Assessments........................................................................................39
7.2.3
Safety Assessments ...........................................................................................40
7.2.4
Pharmacokinetic Assessments ..........................................................................43
7.2.5
Health Economics and Outcomes Research......................................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events..............................................................................................44
8.1.1
Severity Categorization.....................................................................................44
8.1.2
Relationship Categorization..............................................................................45
8.1.3
Outcome Categorization....................................................................................45
8.1.4
Symptoms of the Disease under Study..............................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ...........................................46
8.1.6
Pregnancy..........................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error .............................................46
8.2
Serious Adverse Event Procedures................................................................47
8.2.1
Reference Safety Information ...........................................................................47
8.2.2
Reporting Procedures........................................................................................47
8.2.3
Serious Adverse Event Definition.....................................................................48
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
8.2.4
Serious Adverse Event Collection Time Frame................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates ........................................48
8.2.6
Fatal Outcome...................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting ...................................................................................................49
8.3
Adverse Events of Special Interest................................................................49
8.4
Dose Interruption Criteria..............................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection..............................................................................................51
9.2
Clinical Data Management............................................................................51
9.3
Statistical Analysis Process ...........................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee ........................51
9.5
Sample Size Calculation and Power Considerations.....................................52
9.6
Study Population ...........................................................................................52
9.7
Efficacy Analyses..........................................................................................53
9.7.1
Efficacy Endpoints............................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints...........................................................53
9.8
Safety Analyses .............................................................................................54
9.8.1
Safety Endpoints ...............................................................................................54
9.8.2
Method of Analysis-Safety Endpoints ..............................................................54
9.9
Health Economics and Outcomes Research Analyses ..................................55
9.10
Pharmacokinetics Analyses ...........................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities.............................................................................56
10.1.1
Good Clinical Practice Compliance..................................................................56
10.1.2
Indemnity/Liability and Insurance ....................................................................56
10.1.3
Public Posting of Study Information.................................................................56
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees...................57
10.1.5
Study Suspension, Termination, and Completion.............................................57
10.2
Investigator’s Responsibilities.......................................................................57
10.2.1
Good Clinical Practice Compliance..................................................................57
10.2.2
Protocol Adherence and Investigator Agreement .............................................58
10.2.2.1
Documentation and Retention of Records .............................................58
10.2.2.2
Electronic Case Report Forms................................................................58
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.2.4
Audit/Inspection .....................................................................................59
10.2.2.5
Financial Disclosure...............................................................................59
10.3
Ethical Considerations...................................................................................59
10.3.1
Informed Consent..............................................................................................59
10.3.2
Institutional Review Board or Ethics Committee .............................................60
10.4
Privacy and Confidentiality...........................................................................60
10.5
Study Results/Publication Policy ..................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1
Protocol History.............................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study .............69
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................24
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard 
medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening.  Dysmotility is defined as 
severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-
2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these 
hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-
related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 1.25 mg teduglutide as a 
white lyophilized powder to be reconstituted before use with 0.5 mL sterile water for injection. 
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients. Additional information is provided in the current investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12.  No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures.  Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study.  A copy of the shipping documents 
must be maintained for the investigator’s records.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.   
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0).  Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample.  As such, no claims of significance will be made for any of the data.  
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum.  For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 1.1 (France-specific)
Teduglutide
07 Aug 2018
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

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

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

Sponsor's (Shire) Approval 
Signature: 
, Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Shott Bowel Syndrome Who are Dependent 
on Parenteral Suppmt 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disClosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to patticipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 
Shire
CONFIDENTIAL
Page 2
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
PROTOCOL SIGNATURE PAGE
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD
Mobile Phone: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA phone 
number for medical emergencies.
Emergency Contact 
Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated.   
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of TED-
C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is expected to provide comparable Cmax
concentrations in infants as compared to pediatric patients 
with SBS and was recommended as an evaluation dosing 
regimen in Study SHP633-301.
Section 6.2.5
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES ..................................................................................................................18
BACKGROUND INFORMATION .......................................................................................22
1.
1.1
Short Bowel Syndrome ......................................................................................22
1.2
Teduglutide.........................................................................................................23
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.......................................................................................25
2.2
Study Objectives ................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ............................................................................26
3.1.1
Screening Period ....................................................................................................26
3.1.2
Treatment Period....................................................................................................26
3.1.3
Follow-up Period ...................................................................................................27
3.2
Study Duration ...................................................................................................27
3.3
Sites and Regions ...............................................................................................27
STUDY POPULATION.........................................................................................................28
4.
4.1
Inclusion Criteria................................................................................................28
4.2
Exclusion Criteria...............................................................................................28
4.3
Reproductive Potential .......................................................................................29
4.4
Discontinuation of Subjects ...............................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures......................................................................31
5.2
Concomitant Medications and Procedures.........................................................31
5.3
Permitted Treatment...........................................................................................31
5.4
Prohibited Treatment..........................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
6.1
Identity of Investigational Product.....................................................................32
6.2
Administration of Investigational Product .........................................................32
6.2.1
Interactive Response Technology for Investigational Product Management ........32
6.2.2
Allocation of Subjects to Treatment ......................................................................32
6.2.3
Dosing....................................................................................................................32
6.2.4
Unblinding the Treatment Assignment..................................................................33
6.2.5
Dose Selection Rationale .......................................................................................33
6.3
Labeling, Packaging, and Storage ......................................................................34
6.3.1
Labeling .................................................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability...........................................................................................35
6.5
Subject Compliance............................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule...................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Treatment Period....................................................................................................38
7.1.3
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures .....................................................................38
7.2.1
Demographics and Other Baseline Characteristics................................................38
7.2.2
Efficacy Assessments.............................................................................................39
7.2.3
Safety Assessments................................................................................................40
7.2.4
Pharmacokinetic Assessments ...............................................................................43
7.2.5
Health Economics and Outcomes Research ..........................................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events...................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease under Study ..................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................46
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................46
8.2
Serious Adverse Event Procedures ....................................................................47
8.2.1
Reference Safety Information ................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
8.3
Adverse Events of Special Interest.....................................................................49
8.4
Dose Interruption Criteria ..................................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection...................................................................................................51
9.2
Clinical Data Management.................................................................................51
9.3
Statistical Analysis Process................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee.............................51
9.5
Sample Size Calculation and Power Considerations..........................................52
9.6
Study Population ................................................................................................52
9.7
Efficacy Analyses...............................................................................................53
9.7.1
Efficacy Endpoints.................................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints................................................................53
9.8
Safety Analyses ..................................................................................................54
9.8.1
Safety Endpoints ....................................................................................................54
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .......................................55
9.10
Pharmacokinetics Analyses................................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities .................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities ...........................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement ..................................................57
10.2.3 Documentation and Retention of Records .............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations........................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee ..................................................60
10.4
Privacy and Confidentiality................................................................................60
10.5
Study Results/Publication Policy .......................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1 Protocol History .................................................................................................66
Appendix 2 Guidelines for Nutritional Support Management During the Study ..................69
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................18
Table 2:
Study Schedule: Visits 13-28 ........................................................................20
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will 
capture long-term safety data and provide the opportunity for additional teduglutide treatment.  
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the 
subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV volume, 
calories, days per week, and hours per day. A total 10% of subjects who received teduglutide 
achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for several 
years. Teduglutide treatment also resulted in increases in EN volume and caloric intake as well 
as plasma citrulline. Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose 
groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
parameters. The pharmacokinetic (PK) properties were well characterized in this population and 
were consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated 
by pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening.  Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours.  Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 
to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% 
lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant patients 4 
to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that previously 
observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation Report). In 
addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 12 months (25.6 
to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed in pediatric 
patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with Cmax was 
considered to support teduglutide dose selection since AUCss was previously shown not to 
correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 4 to 
12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within the 
range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures.  Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study.  A copy of the shipping documents 
must be maintained for the investigator’s records.  Kits will be shipped to the site once the 
subject is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample.  As such, no claims of significance will be made for any of the data.  
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum.  For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
Table 2, Section 7.2.2
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
the previous dose.
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 2
Teduglutide
04 Dec 2018
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Amendment 2.1: 04 Dec 2018 (France-specific)
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 
CONFIDENTIAL 
SHP633-301 Protocol Amendment 2.1 (France-specific) 
Teduglutide 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
TDate-: 
I 
I 
Signature: 
.. 
, Global Clinical Develo ment 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Page2 
04 Dec 2018 
-] 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Supp01i 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patiicipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD 
Mobile Phone: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA phone 
number for medical emergencies.
Emergency Contact 
Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated.   
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of TED-
C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is  expected to provide comparable 
Cmax concentrations in infants as compared to pediatric 
patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES ..................................................................................................................18
BACKGROUND INFORMATION .......................................................................................22
1.
1.1
Short Bowel Syndrome ............................................................................................22
1.2
Teduglutide...............................................................................................................23
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ..................................................................................26
3.1.1
Screening Period ........................................................................................26
3.1.2
Treatment Period........................................................................................26
3.1.3
Follow-up Period .......................................................................................27
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................28
STUDY POPULATION.........................................................................................................29
4.
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................31
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Reasons for Discontinuation......................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .....................32
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.
5.1
Prior Medications and Procedures............................................................................33
5.2
Concomitant Medications and Procedures...............................................................33
5.3
Permitted Treatment.................................................................................................33
5.4
Prohibited Treatment................................................................................................33
INVESTIGATIONAL PRODUCT ........................................................................................34
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
6.1
Identity of Investigational Product...........................................................................34
6.2
Administration of Investigational Product ...............................................................34
6.2.1
Interactive Response Technology for Investigational Product 
Management...............................................................................................34
6.2.2
Allocation of Subjects to Treatment ..........................................................34
6.2.3
Dosing........................................................................................................34
6.2.4
Unblinding the Treatment Assignment......................................................35
6.2.5
Dose Selection Rationale ...........................................................................35
6.3
Labeling, Packaging, and Storage ............................................................................36
6.3.1
Labeling .....................................................................................................36
6.3.2
Storage and Handling.................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................39
STUDY PROCEDURES........................................................................................................40
7.
7.1
Study Schedule.........................................................................................................40
7.1.1
Screening....................................................................................................40
7.1.2
Treatment Period........................................................................................40
7.1.3
Follow-up Period .......................................................................................40
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Demographics and Other Baseline Characteristics....................................40
7.2.2
Efficacy Assessments.................................................................................41
7.2.3
Safety Assessments....................................................................................42
7.2.4
Pharmacokinetic Assessments ...................................................................45
7.2.5
Health Economics and Outcomes Research ..............................................45
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..............................................................................46
8.1.2
Relationship Categorization.......................................................................47
8.1.3
Outcome Categorization ............................................................................47
8.1.4
Symptoms of the Disease under Study ......................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations ....................................48
8.1.6
Pregnancy...................................................................................................48
8.1.7
Abuse, Misuse, Overdose, and Medication Error ......................................48
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information ....................................................................49
8.2.2
Reporting Procedures.................................................................................49
8.2.3
Serious Adverse Event Definition .............................................................50
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
8.2.4
Serious Adverse Event Collection Time Frame.........................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................50
8.2.6
Fatal Outcome............................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................51
8.3
Adverse Events of Special Interest...........................................................................51
8.4
Dose Interruption Criteria ........................................................................................52
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................53
9.
9.1
Data Collection.........................................................................................................53
9.2
Clinical Data Management.......................................................................................53
9.3
Statistical Analysis Process......................................................................................53
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................53
9.5
Sample Size Calculation and Power Considerations................................................54
9.6
Study Population ......................................................................................................54
9.7
Efficacy Analyses.....................................................................................................55
9.7.1
Efficacy Endpoints.....................................................................................55
9.7.1.1
Primary Efficacy Endpoint.....................................................................55
9.7.1.2
Secondary Efficacy Endpoints ...............................................................55
9.7.2
Method of Analysis-Efficacy Endpoints....................................................55
9.8
Safety Analyses ........................................................................................................56
9.8.1
Safety Endpoints ........................................................................................56
9.8.2
Method of Analysis-Safety Endpoints.......................................................57
9.9
Health Economics and Outcomes Research Analyses .............................................57
9.10
Pharmacokinetics Analyses......................................................................................57
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................58
10.
10.1
Sponsor’s Responsibilities .......................................................................................58
10.1.1
Good Clinical Practice Compliance...........................................................58
10.1.2
Indemnity/Liability and Insurance.............................................................58
10.1.3
Public Posting of Study Information..........................................................58
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............58
10.1.5
Study Suspension, Termination, and Completion......................................59
10.2
Investigator’s Responsibilities .................................................................................59
10.2.1
Good Clinical Practice Compliance...........................................................59
10.2.2
Protocol Adherence and Investigator Agreement ......................................59
10.2.3
Documentation and Retention of Records .................................................60
10.2.3.1
Electronic Case Report Forms................................................................60
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................60
10.2.3.3
Audit/Inspection .....................................................................................61
10.2.3.4
Financial Disclosure...............................................................................61
10.3
Ethical Considerations..............................................................................................61
10.3.1
Informed Consent.......................................................................................61
10.3.2
Institutional Review Board or Ethics Committee ......................................62
10.4
Privacy and Confidentiality......................................................................................62
10.5
Study Results/Publication Policy .............................................................................63
REFERENCES .......................................................................................................................65
11.
APPENDICES ........................................................................................................................67
12.
Appendix 1
Protocol History.........................................................................................68
Appendix 2
Guidelines for Nutritional Support Management During the Study ..........72
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................18
Table 2:
Study Schedule: Visits 13-28 ........................................................................20
Table 3:
Prohibited Treatment.....................................................................................33
Table 4:
List of Laboratory Tests ................................................................................43
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................44
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects 
in both arms participated in a 2-week minimum screening period, a 24-week treatment 
period, and a 4-week follow-up period. During the screening period, subjects chose into 
which arm to enroll. During the 24-week treatment period, subjects in the SOC treatment 
arm received standard medical therapy for SBS; while those in the teduglutide treatment 
arm received daily subcutaneous (SC) injections of teduglutide (study drug) in addition to 
standard medical therapy. The subjects enrolling in the teduglutide treatment arm were 
randomized 1:1 in a double-blinded manner into 2 parallel dose groups: 0.025 mg/kg/day or 
0.05 mg/kg/day of teduglutide administered subcutaneously for 24 weeks. Compared to the 
SOC, treatment of pediatric subjects with SBS with teduglutide resulted in clinically 
meaningful reductions in PN/IV volume, calories, days per week, and hours per day. A total 
10% of subjects who received teduglutide achieved enteral autonomy within 24 weeks 
despite prior dependence on PN/IV for several years. Teduglutide treatment also resulted in 
increases in EN volume and caloric intake as well as plasma citrulline. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening.  Dysmotility is defined as 
severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12.  No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours.  Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% 
lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant patients 4
to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that previously 
observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation Report). In 
addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 12 months 
(25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed in pediatric 
patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with Cmax was 
considered to support teduglutide dose selection since AUCss was previously shown not to 
correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 4 to 
12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within the 
range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures.  Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study.  A copy of the shipping documents 
must be maintained for the investigator’s records.  Kits will be shipped to the site once the 
subject is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record. The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.   
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0).  Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s)
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample.  As such, no claims of significance will be made for any of the data.  
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum.  For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance.  The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T.,
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact 
Information
Added an exclusion criterion for Gilbert’s disease and liver 
failure based on the values of the transaminases and of total 
bilirubin as requested by Agence Nationale de Sécurité du 
Medicament et des Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace 
residues of tetracycline to be consistent with the European 
Summary of Product Characteristics of teduglutide as 
requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and 
discomfort during procedures such as peripheral venipuncture 
will be implemented.
Section 7.2.3
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
For non-commercial use only

Shire
CONFIDENTIAL
Page 71
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Specified that it is acceptable to only enroll subjects who have 
already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate 
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 72
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 73
SHP633-301 Protocol Amendment 2.1 (France-specific)
Teduglutide
04 Dec 2018
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

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

Shire 
CONFIDENTIAL 
Page2 
SHP633-301 Protocol Amendment 3 
Teduglutide 
24 May 2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
F •ture: 
, MD PhD
I 
I 
, Global Clinical Development 
J 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Phannacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Suppo1t 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Hannonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my paiticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
For non-commercial use only

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

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
24 May 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and 
ileocecal valve, due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome........................................................................................21
1.2
Teduglutide..........................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study........................................................................................24
2.2
Study Objectives..................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart..............................................................................25
3.1.1
Screening Period..................................................................................................25
3.1.2
Treatment Period .................................................................................................25
3.1.3
Follow-up Period.................................................................................................26
3.2
Study Duration.....................................................................................................26
3.3
Sites and Regions ................................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria.................................................................................................27
4.2
Exclusion Criteria................................................................................................27
4.3
Reproductive Potential ........................................................................................28
4.4
Discontinuation of Subjects.................................................................................28
4.4.1
Reasons for Discontinuation................................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit...............................29
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.
5.1
Prior Medications and Procedures.......................................................................30
5.2
Concomitant Medications and Procedures ..........................................................30
5.3
Permitted Treatment ............................................................................................30
5.4
Prohibited Treatment...........................................................................................30
INVESTIGATIONAL PRODUCT ........................................................................................31
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
6.1
Identity of Investigational Product ......................................................................31
6.2
Administration of Investigational Product ..........................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ......31
6.2.2
Allocation of Subjects to Treatment....................................................................31
6.2.3
Dosing..................................................................................................................31
6.2.4
Unblinding the Treatment Assignment ...............................................................32
6.2.5
Dose Selection Rationale.....................................................................................32
6.3
Labeling, Packaging, and Storage .......................................................................33
6.3.1
Labeling...............................................................................................................33
6.3.2
Storage and Handling ..........................................................................................34
6.4
Drug Accountability ............................................................................................34
6.5
Subject Compliance.............................................................................................36
STUDY PROCEDURES........................................................................................................37
7.
7.1
Study Schedule ....................................................................................................37
7.1.1
Screening .............................................................................................................37
7.1.2
Treatment Period .................................................................................................37
7.1.3
Follow-up Period.................................................................................................37
7.2
Study Evaluations and Procedures ......................................................................37
7.2.1
Demographics and Other Baseline Characteristics .............................................37
7.2.2
Efficacy Assessments ..........................................................................................38
7.2.3
Safety Assessments .............................................................................................39
7.2.4
Pharmacokinetic Assessments.............................................................................42
7.2.5
Health Economics and Outcomes Research ........................................................42
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................43
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events....................................................................................................43
8.1.1
Severity Categorization .......................................................................................43
8.1.2
Relationship Categorization ................................................................................44
8.1.3
Outcome Categorization......................................................................................44
8.1.4
Symptoms of the Disease under Study................................................................45
8.1.5
Clinical Laboratory and Other Safety Evaluations..............................................45
8.1.6
Pregnancy ............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error................................................45
8.2
Serious Adverse Event Procedures......................................................................46
8.2.1
Reference Safety Information..............................................................................46
8.2.2
Reporting Procedures ..........................................................................................46
8.2.3
Serious Adverse Event Definition .......................................................................47
8.2.4
Serious Adverse Event Collection Time Frame ..................................................47
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8.2.5
Serious Adverse Event Onset and Resolution Dates...........................................47
8.2.6
Fatal Outcome .....................................................................................................48
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting.................................................................................................48
8.3
Adverse Events of Special Interest......................................................................48
8.4
Dose Interruption Criteria....................................................................................49
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................50
9.
9.1
Data Collection....................................................................................................50
9.2
Clinical Data Management..................................................................................50
9.3
Statistical Analysis Process .................................................................................50
9.4
Planned Interim Analysis, and Data Monitoring Committee ..............................50
9.5
Sample Size Calculation and Power Considerations...........................................51
9.6
Study Population .................................................................................................51
9.7
Efficacy Analyses................................................................................................52
9.7.1
Efficacy Endpoints ..............................................................................................52
9.7.1.1
Primary Efficacy Endpoint.....................................................................52
9.7.1.2
Secondary Efficacy Endpoints ...............................................................52
9.7.2
Method of Analysis-Efficacy Endpoints .............................................................52
9.8
Safety Analyses ...................................................................................................53
9.8.1
Safety Endpoints..................................................................................................53
9.8.2
Method of Analysis-Safety Endpoints.................................................................54
9.9
Health Economics and Outcomes Research Analyses ........................................54
9.10
Pharmacokinetics Analyses .................................................................................54
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................55
10.
10.1
Sponsor’s Responsibilities...................................................................................55
10.1.1
Good Clinical Practice Compliance ....................................................................55
10.1.2
Indemnity/Liability and Insurance ......................................................................55
10.1.3
Public Posting of Study Information ...................................................................55
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees ................55
10.1.5
Study Suspension, Termination, and Completion ...............................................56
10.2
Investigator’s Responsibilities.............................................................................56
10.2.1
Good Clinical Practice Compliance ....................................................................56
10.2.2
Protocol Adherence and Investigator Agreement................................................56
10.2.3
Documentation and Retention of Records...........................................................57
10.2.3.1
Electronic Case Report Forms................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................57
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
10.3
Ethical Considerations.........................................................................................58
10.3.1
Informed Consent ................................................................................................58
10.3.2
Institutional Review Board or Ethics Committee................................................59
10.4
Privacy and Confidentiality.................................................................................59
10.5
Study Results/Publication Policy ........................................................................60
REFERENCES .......................................................................................................................62
11.
APPENDICES ........................................................................................................................64
12.
Appendix 1 Protocol History...................................................................................................65
Appendix 2 Guidelines for Nutritional Support Management During the Study ...................70
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................30
Table 4:
List of Laboratory Tests ................................................................................40
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................41
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately. 
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV volume, 
calories, days per week, and hours per day. A total 10% of subjects who received teduglutide 
achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for several 
years. Teduglutide treatment also resulted in increases in EN volume and caloric intake as well 
as plasma citrulline. Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose 
groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy 
parameters. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
The pharmacokinetic (PK) properties were well characterized in this population and were 
consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated by 
pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits and 
telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. To maintain consistency across centers, guidance and training will be 
provided to help sites follow the nutritional support adjustment guidelines (developed with SBS 
expert input and provided in the protocol) related to decisions for PN reduction and advances in 
enteral feeds based on weight gain, urine and stool output, and clinical stability (Appendix 2). 
Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301. 
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory. Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting. 
Safety labs at telephone visits will be collected at the discretion of the investigator. 
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate. 

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
A copy of the IRB/EC’s written favorable opinion/approval of these documents must be 
provided to the sponsor prior to the start of the study unless it is agreed to and documented 
(abiding by regulatory guidelines and national provisions) prior to study start that another party 
(ie, sponsor or coordinating principal investigator) is responsible for this action. Additionally, if 
the IRB/EC requires modification of the sample subject information and consent document 
provided by the sponsor, the documentation supporting this requirement must be provided to the 
sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register, or market teduglutide; national or local regulatory authorities; and 
the IRB(s)/EC(s) which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Amendment 3
24 May 2019
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without 
exceeding weekly/monthly total blood volume restrictions. 
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic 
parameters will be estimated using a population PK 
modeling approach as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will 
not be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not 
possible in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as 
appropriate is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA 
phone number for medical emergencies.
Emergency Contact Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated. 
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of 
TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is expected to provide comparable 
Cmax concentrations in infants as compared to pediatric 
patients with SBS and was recommended as an evaluation 
Section 6.2.5
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
dosing regimen in Study SHP633-301.
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 71
SHP633-301 Protocol Amendment 3
Teduglutide
24 May 2019
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Amendment 2.1: 04 Dec 2018 (France-specific)
Amendment 3.1: 24 May 2019 (France-specific)
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 
CONFIDENTIAL 
Page 2 
SHP633-301 Protocol Amendment 3.1 (France-specific) 
Teduglutide 
24 May 2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
=e 
l
D_a_ti:-
-j· 
I
, MD PhD
------1 
--
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Shmi Bowel Syndrome Who are Dependent 
on Parenteral Suppmi 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to paiiicipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
te1mination of my paiiicipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD 
Mobile Phone: 
Email: 
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
24 May 2019
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period ........................................................................................25
3.1.2
Treatment Period........................................................................................25
3.1.3
Follow-up Period .......................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation......................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .....................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures............................................................................31
5.2
Concomitant Medications and Procedures...............................................................31
5.3
Permitted Treatment.................................................................................................31
5.4
Prohibited Treatment................................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
6.1
Identity of Investigational Product...........................................................................32
6.2
Administration of Investigational Product ...............................................................32
6.2.1
Interactive Response Technology for Investigational Product 
Management...............................................................................................32
6.2.2
Allocation of Subjects to Treatment ..........................................................32
6.2.3
Dosing........................................................................................................32
6.2.4
Unblinding the Treatment Assignment......................................................33
6.2.5
Dose Selection Rationale ...........................................................................33
6.3
Labeling, Packaging, and Storage ............................................................................34
6.3.1
Labeling .....................................................................................................34
6.3.2
Storage and Handling.................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening....................................................................................................38
7.1.2
Treatment Period........................................................................................38
7.1.3
Follow-up Period .......................................................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographics and Other Baseline Characteristics....................................38
7.2.2
Efficacy Assessments.................................................................................39
7.2.3
Safety Assessments....................................................................................40
7.2.4
Pharmacokinetic Assessments ...................................................................43
7.2.5
Health Economics and Outcomes Research ..............................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................44
8.1.1
Severity Categorization..............................................................................44
8.1.2
Relationship Categorization.......................................................................45
8.1.3
Outcome Categorization ............................................................................45
8.1.4
Symptoms of the Disease under Study ......................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ....................................46
8.1.6
Pregnancy...................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error ......................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information ....................................................................47
8.2.2
Reporting Procedures.................................................................................47
8.2.3
Serious Adverse Event Definition .............................................................48
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
8.2.4
Serious Adverse Event Collection Time Frame.........................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................48
8.2.6
Fatal Outcome............................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................49
8.3
Adverse Events of Special Interest...........................................................................49
8.4
Dose Interruption Criteria ........................................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Statistical Analysis Process......................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................51
9.5
Sample Size Calculation and Power Considerations................................................52
9.6
Study Population ......................................................................................................52
9.7
Efficacy Analyses.....................................................................................................53
9.7.1
Efficacy Endpoints.....................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints....................................................53
9.8
Safety Analyses ........................................................................................................54
9.8.1
Safety Endpoints ........................................................................................54
9.8.2
Method of Analysis-Safety Endpoints.......................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................55
9.10
Pharmacokinetics Analyses......................................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1
Good Clinical Practice Compliance...........................................................56
10.1.2
Indemnity/Liability and Insurance.............................................................56
10.1.3
Public Posting of Study Information..........................................................56
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............56
10.1.5
Study Suspension, Termination, and Completion......................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1
Good Clinical Practice Compliance...........................................................57
10.2.2
Protocol Adherence and Investigator Agreement ......................................57
10.2.3
Documentation and Retention of Records .................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations..............................................................................................59
10.3.1
Informed Consent.......................................................................................59
10.3.2
Institutional Review Board or Ethics Committee ......................................60
10.4
Privacy and Confidentiality......................................................................................60
10.5
Study Results/Publication Policy .............................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1
Protocol History.........................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study ..........70
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects 
in both arms participated in a 2-week minimum screening period, a 24-week treatment 
period, and a 4-week follow-up period. During the screening period, subjects chose into 
which arm to enroll. During the 24-week treatment period, subjects in the SOC treatment 
arm received standard medical therapy for SBS; while those in the teduglutide treatment 
arm received daily subcutaneous (SC) injections of teduglutide (study drug) in addition to 
standard medical therapy. The subjects enrolling in the teduglutide treatment arm were 
randomized 1:1 in a double-blinded manner into 2 parallel dose groups: 0.025 mg/kg/day or 
0.05 mg/kg/day of teduglutide administered subcutaneously for 24 weeks. Compared to the 
SOC, treatment of pediatric subjects with SBS with teduglutide resulted in clinically 
meaningful reductions in PN/IV volume, calories, days per week, and hours per day. A total 
10% of subjects who received teduglutide achieved enteral autonomy within 24 weeks 
despite prior dependence on PN/IV for several years. Teduglutide treatment also resulted in 
increases in EN volume and caloric intake as well as plasma citrulline. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
At all site visits and telephone contacts, safety will be monitored and nutritional support will be 
reviewed and adjusted as needed. To maintain consistency across centers, guidance and training 
will be provided to help sites follow the nutritional support adjustment guidelines (developed 
with SBS expert input and provided in the protocol) related to decisions for PN reduction and 
advances in enteral feeds based on weight gain, urine and stool output, and clinical stability 
(Appendix 2). Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory. Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting. 
Safety labs at telephone visits will be collected at the discretion of the investigator. 
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s)
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate. 

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Amendment 3.1
24 May 2019
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly 
total blood volume restrictions. 
Synopsis, Table 1, Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples 
could be collected without exceeding weekly/monthly total blood 
volume restrictions.
Synopsis, Table 1, Section 3.1.2, 
Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be 
taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small 
bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape 
criteria, the assessments scheduled for the EOS visit should be 
conducted.
Synopsis, Table 2, Section 3.1.3, 
Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age 
at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit 
to reduce site burden.
Synopsis, Table 1, Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide 
concentration values. Pharmacokinetic parameters will be estimated 
using a population PK modeling approach as appropriate and reported 
separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, Section 7.2.5, 
Section 9.9
Clarified that native GLP-2 samples drawn while subjects are receiving 
teduglutide should be drawn at least 14 hours after the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and parenteral 
nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not be 
supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who have already 
had an upper GI series with small bowel follow through performed 
since the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native GLP-2.
Table 5
Removed references to subject assent as assent is not possible in a study 
of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate is part of 
the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact Information
Added an exclusion criterion for Gilbert’s disease and liver failure 
based on the values of the transaminases and of total bilirubin as 
requested by Agence Nationale de Sécurité du Medicament et des 
Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace residues of 
tetracycline to be consistent with the European Summary of Product 
Characteristics of teduglutide as requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and discomfort 
during procedures such as peripheral venipuncture will be implemented.
Section 7.2.3
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical Monitor a 
copy of the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 
is now retired; a copy of the form must be sent by email only.
Updated emergency contact information to reflect the change of Shire 
medical monitor to 
, IQVIA back up medical support 
to 
, and IQVIA phone number for medical 
emergencies.
Emergency Contact Information
A single email address (
) is now used to report a 
Product Quality Complaint, independently from where it has originated. 
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve enteral 
autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, Section 
9.7.2
Updated  the information on the clinical studies with teduglutide in 
pediatric subjects to include the results of TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for this study.
Section 6.1
Updated the dose selection rationale with results from a simulation 
work using the previous population pharmacokinetic model. Based on 
the totality of clinical data, 0.05 mg/kg once daily is  expected to 
provide comparable Cmax concentrations in infants as compared to 
pediatric patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, Section 
8.2.4
Added heart failure with severe fluid overload, determined by the 
sponsor or investigator to be related to the investigational product, to 
the list of events leading to interruption of investigational product 
administration. This addition is in alignment with the warnings and 
special precautions listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar 
days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout the protocol
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 71
SHP633-301 Protocol Amendment 3.1 (France-specific)
Teduglutide
24 May 2019
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

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

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

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

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

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

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

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period ....................................................................................................25
3.1.2
Treatment Period....................................................................................................25
3.1.3
Follow-up Period ...................................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................27
STUDY POPULATION.........................................................................................................28
4.
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures............................................................................31
5.2
Concomitant Medications and Procedures...............................................................31
5.3
Permitted Treatment.................................................................................................31
5.4
Prohibited Treatment................................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
6.1
Identity of Investigational Product...........................................................................32
6.2
Administration of Investigational Product ...............................................................32
6.2.1
Interactive Response Technology for Investigational Product Management ........32
6.2.2
Allocation of Subjects to Treatment ......................................................................32
6.2.3
Dosing....................................................................................................................32
6.2.4
Unblinding the Treatment Assignment..................................................................33
6.2.5
Dose Selection Rationale .......................................................................................33
6.3
Labeling, Packaging, and Storage ............................................................................34
6.3.1
Labeling .................................................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Treatment Period....................................................................................................38
7.1.3
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographics and Other Baseline Characteristics................................................38
7.2.2
Efficacy Assessments.............................................................................................39
7.2.3
Safety Assessments................................................................................................40
7.2.4
Pharmacokinetic Assessments ...............................................................................44
7.2.5
Health Economics and Outcomes Research ..........................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................47
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest...........................................................................50
8.4
Dose Interruption Criteria ........................................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Statistical Analysis Process......................................................................................52
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................52
9.5
Sample Size Calculation and Power Considerations................................................53
9.6
Study Population ......................................................................................................53
9.7
Efficacy Analyses.....................................................................................................54
9.7.1
Efficacy Endpoints.................................................................................................54
9.7.1.1
Primary Efficacy Endpoint.....................................................................54
9.7.1.2
Secondary Efficacy Endpoints ...............................................................54
9.7.2
Method of Analysis-Efficacy Endpoints................................................................54
9.8
Safety Analyses ........................................................................................................55
9.8.1
Safety Endpoints ....................................................................................................55
9.8.2
Method of Analysis-Safety Endpoints...................................................................56
9.9
Health Economics and Outcomes Research Analyses .............................................56
9.10
Pharmacokinetics Analyses......................................................................................56
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................57
10.
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Indemnity/Liability and Insurance.........................................................................57
10.1.3 Public Posting of Study Information......................................................................57
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................57
10.1.5 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement ..................................................58
10.2.3 Documentation and Retention of Records .............................................................59
10.2.3.1
Electronic Case Report Forms................................................................59
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
10.2.3.3
Audit/Inspection .....................................................................................60
10.2.3.4
Financial Disclosure...............................................................................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board or Ethics Committee ..................................................61
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................62
REFERENCES .......................................................................................................................64
11.
APPENDICES ........................................................................................................................66
12.
Appendix 1
Protocol History .....................................................................................67
Appendix 2
Guidelines for Nutritional Support Management During the Study ......70
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................42
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................43
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to 
enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment 
arm may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is 
met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 (2 hours±10 minutes postdose). At baseline, safety 
labs and PK will be separated by 1 day.
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study if 
that study is open to enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide 
treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least one of the 
following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time points.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 
20% reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and will 
be reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription and 
adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition;
PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK will be separated by 1 day. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the 
teduglutide treatment arm, PT and INR will be tested at screening, and repeated if clinically indicated. Hematology is not collected at Week 1 or at telephone visits.  Hematology 
will not be collected at screening for subjects who weigh <7 kg. C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects who 
weigh <7 kg.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). The predose sample 
will not be collected from subjects who weigh <7 kg. Subjects also will have blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of 
the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments.
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription 
and adjust nutritional 
support as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational 
product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study if that study is open to enrollment at the time of the SHP633-301 EOS; if subjects require treatment before the end of the 
4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly 
total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
Note: (X) denotes optional assessments.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al., 
2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in 
all dosing cohorts. There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported. No discontinuations from 
study were due to adverse events (AEs). Additional studies in pediatric patients with SBS are
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects
with SBS with teduglutide resulted in clinically meaningful reductions in PN volume, calories, 
days per week, and hours per day. A total 10% of subjects who received teduglutide achieved 
enteral autonomy within 24 weeks despite prior dependence on PN for several years. Teduglutide 
treatment also resulted in increases in EN volume and caloric intake as well as plasma citrulline. 
Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
The pharmacokinetic (PK) properties were well characterized in this population and were 
consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated by 
pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to enrollment at the time 
of the SHP633-301 EOS that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. 
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed immediately 
to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits.
Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits and 
telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. To maintain consistency across centers, guidance and training will be 
provided to help sites follow the nutritional support adjustment guidelines (developed with SBS 
expert input and provided in the protocol) related to decisions for PN reduction and advances in 
enteral feeds based on weight gain, urine and stool output, and clinical stability (Appendix 2). 
Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour±10 minutes and 4 hours±10 minutes postdose) and at Week 7 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted  using data from 8 adult
clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as 
study TED-C13-003 and suggested that the same adult dose (0.05mg/kg) be used in pediatric 
subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301. 
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. 
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigational 
product.
At the discretion of the investigator, subjects who fail screening may be rescreened one time with 
prior sponsor approval. In the event of rescreening, the subject should be reconsented, a new 
subject number assigned, and all screening procedures (except UGI/SBFT if performed within 
2 months prior to rescreening) should be repeated.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight)=1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
Prescribed Parenteral Nutrition
The prescribed PN weekly total volume and days per week will be recorded. Changes in PN 
prescription that reflect changes in the subject's intestinal absorption are recorded.  
Temporary adjustments to PN that last less than 72 hours should be recorded as concomitant 
medications, not a PN adjustments.  Examples include fluid resuscitation during treatment 
of sepsis or acute gastroenteritis, and modification of PS due to interruption of entral venous 
access.  
Parenteral nutrition prescriptions that last more than 72 hours should be recorded as PN 
adjustments.  Examples include recurrent replacement of fluid losses, titration of PN due to 
changes in intestinal absorptive function, and discontinuation of PN due to achievement of 
enteral autonomy.
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central 
laboratory or a local laboratory. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Local lab results are not required to be entered in the eCRFs; however, if the local lab results 
indicate any new clinically significant changes, they must be reported as an adverse event (see 
Section 8). Urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK will be separated by 1 day. The predose 
sample will not be collected from subjects who weigh <7 kg.
Safety labs at telephone visits will be collected at the discretion of the investigator. 
Hematology will not be collected at Week 1 or at telephone visits. Hematology will not be 
collected at screening for subjects <7 kg.
For all subjects, prothrombin time (PT) and international normalized ratio (INR), tested at 
screening, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive proteinc

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
b For all subjects, PT and INR will be tested at screening and repeated only if clinically indicated.
c C-reactive protein will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample Volume 
(mL)
No. Samples for 
Subjects > 7kg
Total Volume 
(mL)
Subjects Receiving Teduglutide Treatment
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Antibodies
2.0
3
6.0
Pharmacokineticsd
2.0
4
8.0
Native GLP-2e
1.5
2
3
Total mL:
56.9
Subjects Receiving Standard of Care
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Native GLP-2 e
1.5
2
3.0
Total mL:
42.9
CRP=C-reactive protein; GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
a C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
b Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
c PT and INR tested at screening only, repeat while on study only if clinically indicated.
dAt baseline, safety labs and PK will be separated by 1 day.  Baseline: 3 timepoints; The predose sample will not be collected 
from subjects who weigh <7 kg. Week 7: 1 timepoint.
e Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
Note: The amount of blood to be drawn for each assessment is an estimate. Blood volume 
estimates do not include safety labs performed after PN adjustments.  
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will 
include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and 
body temperature (°C/°F). Blood pressure should be determined by the appropriate size 
cuff (using the same method, the same leg, and in the supine position throughout the 
study, when possible). 
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Blood pressure measurements should be attempted as part of the vital signs, but lack of blood 
pressure results will not constitute a protocol deviation. New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 
1 hour±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). At baseline, safety 
labs and PK will be separated by 1 day.  Subjects also will have blood samples taken for 
teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of the treatment 
period. Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a 
central line. The site of teduglutide administration prior to PK blood draws (arm, thigh, 
abdomen) must be specified as well as the exact date and time of the sample. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
Interim analysis will be conducted for regulatory submissions, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned, and no hypotheses will be formally 
tested.  Due to the open-label nature of this study, personnel involved in conducting the interim 
analyses will have access to treatment assignments. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.  

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and will be reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register, or market teduglutide; national or local regulatory authorities; and 
the IRB(s)/EC(s) which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
APPENDICES
12.
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Amendment 3
24 May 2019
Global
Amendment 4
17 Dec 2019
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1.1, 
Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly total 
blood volume restrictions. 
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples could 
be collected without exceeding weekly/monthly total blood volume 
restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be taken 
within ±10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small bowel 
ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape criteria, 
the assessments scheduled for the EOS visit should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age at 
screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit to 
reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide concentration 
values. Pharmacokinetic parameters will be estimated using a population 
PK modeling approach as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions questionnaire 
to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
For non-commercial use only

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

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
Updated the dose selection rationale with results from a simulation work 
using the previous population pharmacokinetic model. Based on the totality 
of clinical data, 0.05 mg/kg once daily is expected to provide comparable 
Cmax concentrations in infants as compared to pediatric patients with SBS 
and was recommended as an evaluation dosing regimen in Study SHP633-
301.
Section 6.2.5
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by the sponsor 
or investigator to be related to the investigational product, to the list of 
events leading to interruption of investigational product administration. 
This addition is in alignment with the warnings and special precautions 
listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
24 May 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

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

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

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

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

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

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

Shire
CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES..................................................................................................................17
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
2.
OBJECTIVES.........................................................................................................................24
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period....................................................................................................25
3.1.2
Treatment Period....................................................................................................25
3.1.3
Follow-up Period ...................................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Discontinuation of Subjects .....................................................................................29
4.3.1
Reasons for Discontinuation..................................................................................29
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Medications and Procedures............................................................................30
5.2
Concomitant Medications and Procedures...............................................................30
5.3
Permitted Treatment.................................................................................................30
5.4
Prohibited Treatment................................................................................................30
6.
INVESTIGATIONAL PRODUCT ........................................................................................31
6.1
Identity of Investigational Product...........................................................................31
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
6.2
Administration of Investigational Product ...............................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ........31
6.2.2
Allocation of Subjects to Treatment ......................................................................31
6.2.3
Dosing....................................................................................................................31
6.2.4
Unblinding the Treatment Assignment..................................................................32
6.2.5
Dose Selection Rationale.......................................................................................32
6.3
Labeling, Packaging, and Storage............................................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Storage and Handling.............................................................................................34
6.4
Drug Accountability.................................................................................................34
6.5
Subject Compliance..................................................................................................36
7.
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Screening................................................................................................................37
7.1.2
Treatment Period....................................................................................................37
7.1.3
Follow-up Period ...................................................................................................37
7.2
Study Evaluations and Procedures ...........................................................................37
7.2.1
Demographics and Other Baseline Characteristics................................................37
7.2.2
Efficacy Assessments.............................................................................................38
7.2.3
Safety Assessments................................................................................................39
7.2.4
Pharmacokinetic Assessments ...............................................................................43
7.2.5
Health Economics and Outcomes Research ..........................................................43
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease under Study ..................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................46
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
8.3
Adverse Events of Special Interest...........................................................................49
8.4
Dose Interruption Criteria ........................................................................................50
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Statistical Analysis Process......................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................51
9.5
Sample Size Calculation and Power Considerations................................................52
9.6
Study Population ......................................................................................................52
9.7
Efficacy Analyses.....................................................................................................53
9.7.1
Efficacy Endpoints.................................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints................................................................53
9.8
Safety Analyses........................................................................................................54
9.8.1
Safety Endpoints....................................................................................................54
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................55
9.10
Pharmacokinetics Analyses......................................................................................55
10. SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement..................................................57
10.2.3 Documentation and Retention of Records.............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................59
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations..............................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee..................................................60
10.4
Privacy and Confidentiality......................................................................................60
11. REFERENCES .......................................................................................................................63
12. APPENDICES ........................................................................................................................65
Appendix 1
Protocol History .....................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study ......70
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................30
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to 
enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment 
arm may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is 
met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).  At baseline, 
safety labs and PK will be separated by 1 day.
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study if 
that study is open to enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide 
treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least one of the 
following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time points.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and will 
be reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription and 
adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 12
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition;
PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK will be separated by 1 day. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the 
teduglutide treatment arm, PT and INR will be tested at screening, and repeated if clinically indicated.  Hematology is not collected at Week 1 or at telephone visits.  Hematology 
will not be collected at screening for subjects who weigh <7 kg. C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects who 
weigh <7 kg.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). The predose sample 
will not be collected from subjects who weigh <7 kg. Subjects also will have blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of 
the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments.
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription 
and adjust nutritional 
support as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Table 2:
Study Schedule: Visits 13-28
Procedures
Week 
13
Week 
14
Week 
15
Week 
16
Week 
17
Week 
18
Week 
19
Week 
20
Week 
21
Week 
22
Week 
23
Week 24 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational 
product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study if that study is open to enrollment at the time of the SHP633-301 EOS; if subjects require treatment before the end of the 
4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly 
total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
Note: (X) denotes optional assessments.
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
1.
BACKGROUND INFORMATION
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN volume, calories, 
days per week, and hours per day. A total 10% of subjects who received teduglutide achieved 
enteral autonomy within 24 weeks despite prior dependence on PN for several years. Teduglutide 
treatment also resulted in increases in EN volume and caloric intake as well as plasma citrulline. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
2.
OBJECTIVES
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to enrollment at the time 
of the SHP633-301 EOS that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. 
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed immediately 
to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
At all site visits and telephone contacts, safety will be monitored and nutritional support will be 
reviewed and adjusted as needed. To maintain consistency across centers, guidance and training 
will be provided to help sites follow the nutritional support adjustment guidelines (developed 
with SBS expert input and provided in the protocol) related to decisions for PN reduction and 
advances in enteral feeds based on weight gain, urine and stool output, and clinical stability 
(Appendix 2). Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
4.
STUDY POPULATION
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Reproductive Potential 
Not applicable; this study will enroll infants.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
4.3
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.3.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted using data from 8 adult 
clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as study 
TED-C13-003 and suggested that the same adult dose (0.05mg/kg) be used in pediatric subjects 
(aged between 1.67-14.7 years) (Marier et al., 2017).
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
7.
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. 
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigational 
product.
At the discretion of the investigator, subjects who fail screening may be rescreened one time with 
prior sponsor approval. In the event of rescreening, the subject should be reconsented, a new 
subject number assigned, and all screening procedures (except UGI/SBFT if performed within 
2 months prior to rescreening) should be repeated.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight)=1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
Prescribed Parenteral Nutrition
The prescribed PN weekly total volume and days per week will be recorded. Changes in PN 
prescription that reflect changes in the subject's intestinal absorption are recorded.  
Temporary adjustments to PN that last less than 72 hours should be recorded as concomitant 
medications, not a PN adjustments.  Examples include fluid resuscitation during treatment 
of sepsis or acute gastroenteritis, and modification of PS due to interruption of entral venous 
access.  
Parenteral nutrition prescriptions that last more than 72 hours should be recorded as PN 
adjustments.  Examples include recurrent replacement of fluid losses, titration of PN due to 
changes in intestinal absorptive function, and discontinuation of PN due to achievement of 
enteral autonomy.
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 
5 to 7 days after a PN adjustment. Safety labs performed after PN adjustment and between site 
visits will consist of clinical chemistry and urinalysis and may be processed by the central 
laboratory or a local laboratory. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Local lab results are not required to be entered in the eCRFs; however, if the local lab results 
indicate any new clinically significant changes, they must be reported as an adverse event (see 
Section 8). Urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK will be separated by 1 day. The predose 
sample will not be collected from subjects who weigh <7 kg.
Safety labs at telephone visits will be collected at the discretion of the investigator. 
Hematology will not be collected at Week 1 or at telephone visits. Hematology will not be 
collected at screening for subjects <7 kg.
For all subjects, prothrombin time (PT) and international normalized ratio (INR), tested at 
screening, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive proteinc

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
c C-reactive protein will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample Volume 
(mL)
No. Samples for 
Subjects >7 kg
Total Volume 
(mL)
Subjects Receiving Teduglutide Treatment
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Antibodies
2.0
3
6.0
Pharmacokineticsd
2.0
4
8.0   
Native GLP-2e
1.5
2
3.0
Total mL:
56.9
Subjects Receiving Standard of Care
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Native GLP-2 e
1.5
2
3.0
Total mL:
42.9
CRP=C-reactive protein; GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
a C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
b Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
c PT and INR tested at screening only, repeat while on study only if clinically indicated.
dAt baseline, safety labs and PK will be separated by 1 day.  Baseline: 3 timepoints; The predose sample will not be collected 
from subjects who weigh <7 kg. Week 7: 1 timepoint.
e Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
Note: The amount of blood to be drawn for each assessment is an estimate. Blood volume 
estimates do not include safety labs performed after PN adjustments.  
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.  
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). At baseline, safety labs and 
PK will be separated by 1 day. Subjects also will have blood samples taken for teduglutide PK 
analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment 
period. Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a 
central line. The site of teduglutide administration prior to PK blood draws (arm, thigh, 
abdomen) must be specified as well as the exact date and time of the sample. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
Interim analysis will be conducted for regulatory submissions, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned and no hypotheses will be formally 
tested.  Due to the open-label nature of this study, personnel involved in conducting the interim 
analyses will have access to treatment assignments. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.  

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to 
week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
Due to the limited size of the study population, descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables will be summarized using descriptive statistics including number of 
subjects, mean, median, standard deviation, maximum, and minimum. For categorical variables, 
statistical summaries will include number of subjects and percentages.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and will be reported separately.
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
10.
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from 
the sponsor. The following information is collected: any significant payments from the 
sponsor or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
11.
REFERENCES
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
12.
APPENDICES
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Amendment 3.1
24 May 2019
France-specific
Amendment 4.1
17 Dec 2019
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly total 
blood volume restrictions. 
Synopsis, Table 1, Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples 
could be collected without exceeding weekly/monthly total blood volume 
restrictions.
Synopsis, Table 1, Section 3.1.2, 
Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be 
taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small bowel 
ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape 
criteria, the assessments scheduled for the EOS visit should be conducted.
Synopsis, Table 2, Section 3.1.3, 
Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age at 
screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit to 
reduce site burden.
Synopsis, Table 1, Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide 
concentration values. Pharmacokinetic parameters will be estimated using 
a population PK modeling approach as appropriate and reported 
separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, Section 7.2.5, 
Section 9.9
Clarified that native GLP-2 samples drawn while subjects are receiving 
teduglutide should be drawn at least 14 hours after the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and parenteral 
nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not be 
supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who have already
had an upper GI series with small bowel follow through performed since 
the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native GLP-2.
Table 5
Removed references to subject assent as assent is not possible in a study 
of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate is part of 
the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol.
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact Information
Added an exclusion criterion for Gilbert’s disease and liver failure 
based on the values of the transaminases and of total bilirubin as 
requested by Agence Nationale de Sécurité du Medicament et des 
Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace residues of 
tetracycline to be consistent with the European Summary of Product 
Characteristics of teduglutide as requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and discomfort 
during procedures such as peripheral venipuncture will be implemented.
Section 7.2.3
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical Monitor a 
copy of the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 
is now retired; a copy of the form must be sent by email only.
Updated emergency contact information to reflect the change of Shire 
medical monitor to 
, IQVIA back up medical support 
to 
, and IQVIA phone number for medical 
emergencies.
Emergency Contact Information
A single email address (
) is now used to report a 
Product Quality Complaint, independently from where it has originated.  
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve enteral 
autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with teduglutide in 
pediatric subjects to include the results of TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for this study.
Section 6.1
Updated the dose selection rationale with results from a simulation 
work using the previous population pharmacokinetic model. Based on 
the totality of clinical data, 0.05 mg/kg once daily is  expected to 
provide comparable Cmax concentrations in infants as compared to 
pediatric patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by the 
sponsor or investigator to be related to the investigational product, to 
the list of events leading to interruption of investigational product 
administration. This addition is in alignment with the warnings and
special precautions listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar 
days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout the protocol
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
24 May 2019
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
Adjustments should be based on the actual nutritional support in volume and calories the subject 
infuses. Subjects should remain compliant with the nutritional support prescription in volume 
and calories during the study.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only

Shire
CONFIDENTIAL
Page 71
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only