Clinical trial NCT02340819
Conditions: Short Bowel Syndrome
Sponsor: Shire
Start date: 2014-12-18; Completion date: 2018-11-05
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of an investigational treatment (teduglutide) in Japanese patients with PN-dependent SBS. This study will also look at how teduglutide moves through the body (pharmacokinetics).

Detailed description:

Arms: arm 1: 0.05 mg/kg/day administered by subcutaneous injection over a 24-week period.
Interventions: intervention 1: Teduglutide
Intervention descriptions: intervention 1: 0.05 mg/kg/day administered by subcutaneous injection over a 24-week period.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02340819 
 
Study Title:  
A 4-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome 
 
 
Study Number:  
TED-C14-004 
 
Protocol Version and Date:  
 
Protocol v1.0: 05 August 2014 
Protocol v2.0, Amendment 1: 20 August 2014 (administrative amendment) 
Protocol v3.0, Amendment 1 (corrected): 15 September 2014 
Protocol v4.0, Amendment 2: 03 March 2015 
Protocol v5.0, Amendment 3: 17 November 2015 
Protocol v6.0, Amendment 4: 03 April 2017 


TEDUGLUTIDE (ALX-0600)
A 3-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 1.0
Phase 3
Sponsor:  NPS Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
Medical Monitor (Medical Expert of the Sponsor):
 MD
 Clinical Development
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-1-3, Korau, Bunkyo-ku,
Tokyo 112-0004, Japan
TEL
FAX:
Protocol v1.0:
05 August 2014
The information contained in this document is the property of NPS Pharmaceuticals, Inc. It is 
understood that the information will not be disclosed to others aside from the investigator(s) 
and duly designated staff, applicable IRB(s) and regulatory authorities without prior written 
approval from NPS Pharmaceuticals Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the study drug may be administered.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 2 of 77
Final v1.0
05 August 2014
SUMMARY
Protocol TED-C14-004
Title of Study: A 3-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 3-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous volume (PN/I.V.) support optimization period; and a 
stabilization period in which stable administration of PN/I.V. support, defined as a targeted 
urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and nourished,
is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a subject fails to 
remain stable for at least 4 consecutive weeks, the subject may start the optimization period 
again, beginning with Visit 1.1. Those subjects who fail to stabilize after 2 attempts will not 
proceed further and will not be dosed. Stage 2 will be a dosing period of 24 weeks, during 
which subjects will self-administer the study drug at home.
Stage 3 is the long-term extension portion of the study, which will begin immediately 
following Stage 2.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 
24 months or until regulatory approval and commercial availability of teduglutide in Japan. 
(After the approval of marketing authorization, the study will continue as a post-marketing 
clinical study until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled during the recruitment 
period, which ends approximately 6 months after the initiation of the study.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 3 of 77
Final v1.0
05 August 2014
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:
o
Actual PN/I.V. usage matches prescribed PN/I.V.
o
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.
o
Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function: 
o
Total bilirubin < 2 times upper limit of normal (ULN)
o
Aspartate aminotransferase (AST) < 5 times ULN
o
Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function:
o
Serum creatinine < 2 times ULN
o
Creatinine clearance ≥50 mL/minute

Adequate pancreatic function:
o
Serum amylase < 2 times ULN
o
Serum lipase < 2 times ULN


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 4 of 77
Final v1.0
05 August 2014

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC)
injection is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile 
water for injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study.
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen or either thigh or arm. The first SC injection should be administered under the 
supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period; and a stabilization period that demonstrates stable administration 
of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks (total maximum
16 weeks for optimization/stabilization periods).  Subjects who fail optimization may repeat 
this period (taking up to an additional 16 weeks).  Therefore the total possible duration of 
Stage 1 is up to 33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue in the extension 
treatment period for up to an additional 24 months (Stage 3) or until teduglutide is 
commercially available, whichever comes first. (After the approval of marketing 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 5 of 77
Final v1.0
05 August 2014
authorization, the study will continue as a post-marketing clinical study in order to 
continuously provide teduglutide to the subjects until the product is commercially available).
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stage 3:  Absolute and percent change from baseline in 
weekly PN/I.V. volume and changes in days per week of PN/I.V. support and plasma 
citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose pharmacokinetics will be evaluated on the 
first day of teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected 
pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
Safety – All Stages:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, 
laboratory safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 6 of 77
Final v1.0
05 August 2014
changes in urine output (48-hour I/O), body weight and body mass index (BMI) will be 
evaluated.  An abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will 
be done at the end of the optimization period if these procedures were not done in the 
6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated at the end of the 
main treatment period (Stage 2) and at the end of the extension treatment period (Stage 3).  
For all subjects with a history of Crohn’s disease, an upper gastrointestinal (GI) contrast series 
with small bowel follow through will be performed during the stabilization period, prior to the 
baseline visit.
Statistical methods:  No formal testing will be conducted for efficacy variables.  For 
continuous variables, descriptive statistics will be used to summarize median, maximum, 
minimum, mean (± standard deviation [SD]), geometric mean (± standard error [SE]) and its 
95% confidence interval.  For categorical variables, n (%) will be summarized.  Individual 
data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the 
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.




Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 8 of 77
Final v1.0
05 August 2014
Reviewed and Approved:
EPS Associate Co., Ltd.
2-1-3, Korau, Bunkyo-ku
Tokyo 112-0004, Japan
Signature
Date 
(DD MMM YYYY)
Reviewed:
Japan


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 9 of 77
Final v1.0
05 August 2014
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................1
SUMMARY ....................................................................................................................................2
SIGNATURE PAGE......................................................................................................................7
TABLE OF CONTENTS ..............................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................14
1
INTRODUCTION..................................................................................................................16
1.1
Background.....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design.............................................................................................19
2
OBJECTIVES ........................................................................................................................19
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2 ....................................................19
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3 ....................................................20
2.3
Pharmacokinetic Endpoints – Stage 2 Only....................................................................20
2.4
Safety Objectives – All Stages........................................................................................20
3
STUDY DESIGN....................................................................................................................21
3.1
Main Treatment Period (Stages 1 and 2) ........................................................................21
3.2
Extension Treatment Period (Stage 3)............................................................................21
4
SUBJECT SELECTION AND PARTICIPATION............................................................24
4.1
Number of Subjects.........................................................................................................24
4.2
Inclusion Criteria ............................................................................................................24
4.2.1
Inclusion in Stage 3..........................................................................................25
4.3
Exclusion Criteria ...........................................................................................................25
4.4
Subject Withdrawal Criteria ...........................................................................................28
4.4.1
Events Necessitating Withdrawal from Study.................................................28
4.4.2
Re-screening of Subjects..................................................................................29
5
TREATMENTS AND TREATMENT PLAN .....................................................................29
5.1
Treatments Administered................................................................................................30
5.1.1
Identification of Investigational Product .........................................................30


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 10 of 77
Final v1.0
05 August 2014
5.1.2
Packaging and Labeling...................................................................................30
5.1.3
Storage, Accountability, and Stability.............................................................31
5.2
Dose Regimen.................................................................................................................31
5.2.1
Selection of Doses in Study.............................................................................31
5.2.2
Selection and Timing of Dose for Each Subject..............................................32
5.2.3
Subjects Who Achieve PN/I.V. Independence ................................................32
5.2.4
Compliance with Dosing Regimens.................................................................33
5.3
Prior and Concomitant Medications ...............................................................................33
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................33
6.1
Efficacy Evaluations.......................................................................................................33
6.2
Safety Evaluations ..........................................................................................................34
6.2.1
Adverse Events ................................................................................................34
6.2.2
Serious Adverse Events ...................................................................................37
6.2.3
Pregnancy Reporting........................................................................................40
6.2.4
Laboratory Evaluations....................................................................................40
6.2.5
Plasma Citrulline..............................................................................................42
6.2.6
Women of Child Bearing Potential..................................................................42
6.2.7
48-Hour Oral Fluid Intake and Urine Output ..................................................42
6.2.8
Clinical Assessment of Crohn’s Disease Activity ...........................................43
6.2.9
Subject Diaries.................................................................................................43
6.2.10
Changes in PN/I.V. Volume ............................................................................43
6.2.11
Medical History and Demographics ................................................................43
6.2.12
Concomitant Medication Assessment..............................................................44
6.2.13
Physical Examinations.....................................................................................44
6.2.14
Vital Signs and Body Weight ..........................................................................44
6.2.15
Electrocardiograms ..........................................................................................44
6.2.16
Gastrointestinal-specific Testing .....................................................................45
6.3
Pharmacokinetic Evaluations..........................................................................................45
6.4
Schedule of Evaluations and Procedures........................................................................46
7
DATA MANAGEMENT.......................................................................................................53
7.1
Data Collection ...............................................................................................................53
7.2
Record Retention ............................................................................................................54


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 11 of 77
Final v1.0
05 August 2014
7.3
Quality Control ...............................................................................................................54
8
STATISTICAL METHODOLOGY.....................................................................................55
8.1
Demographic and Baseline Variables.............................................................................55
8.2
Efficacy and Pharmacodynamic Variables .....................................................................55
8.2.1
Efficacy and Pharmacodynamics – Stage 2.....................................................55
8.2.2
Efficacy and Pharmacodynamics – Stage 3.....................................................57
8.3
Safety – All Stages..........................................................................................................57
8.3.1
Statistical Methods for Safety Variables..........................................................57
8.4
Pharmacokinetic Variables – Stage 2 Only ....................................................................57
8.5
Analysis Populations, Data Sets, and Time Points .........................................................57
8.5.1
Analysis Populations........................................................................................57
8.6
Statistical/Analytical Issues ............................................................................................58
8.6.1
Adjustments for Covariates..............................................................................58
8.6.2
Handling of Dropouts or Missing Data............................................................58
8.6.3
Interim Analyses ..............................................................................................58
8.6.4
Multiple Comparisons/Multiplicity .................................................................58
8.6.5
Use of an Efficacy Subset of Subjects.............................................................58
8.6.6
Examination of Subgroups...............................................................................58
8.7
Determination of Sample Size ........................................................................................58
8.8
Changes to Planned Statistical Analyses ........................................................................59
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................59
9.1
Declaration of Helsinki and Ethical Review...................................................................59
9.2
Subject Information and Consent....................................................................................59
9.3
Subject Data Protection...................................................................................................60
9.4
Payment and Compensation............................................................................................60
9.5
Changes to the Protocol ..................................................................................................60
9.6
Confidentiality/Publication of the Study ........................................................................61
9.7
Study Termination ..........................................................................................................61
10 REFERENCES.......................................................................................................................62
APPENDIX 1:
PN/I.V. OPTIMIZATION.............................................................................63


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 12 of 77
Final v1.0
05 August 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2).............................................................................................................65
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3) .................................................................................69
A. STUDY ORGANIZATION....................................................................................................72
B. LIST OF PRINCIPAL INVESTIGATORS AND INVESTIGATIONAL SITES ............74
C. LIST OF CLINICAL RESEARCH ASSOCIATES ............................................................75
D. DURATION OF THE STUDY ..............................................................................................76
E. PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE............................77




Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 14 of 77
Final v1.0
05 August 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NPS
NPS Pharmaceuticals, Inc.
PI
Principal Investigator
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 15 of 77
Final v1.0
05 August 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
PN/I.V.
Parenteral Nutrition/Intravenous (volume)
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SMT
Safety Management Team
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 16 of 77
Final v1.0
05 August 2014
1
INTRODUCTION
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 17 of 77
Final v1.0
05 August 2014
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats. In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 18 of 77
Final v1.0
05 August 2014
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.
Clinical Studies
Results of the pivotal study filed for the US New Drug Application, CL0600-020, showed that 
teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing 
parenteral nutrition/intravenous (PN/I.V.) volume in adult subjects with SBS.  In this study the 
responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects achieving a 
mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and in the United States (US).  The clinical 
profile and issues related to SBS and PN/I.V. in Japan are similar to those in the EU and in the 
US.    Therefore, there is an unmet medical need for Japanese patients with PN-dependent SBS.  
This study is designed to provide evidence of safety and efficacy of teduglutide in a Japanese 
SBS patient population. 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 19 of 77
Final v1.0
05 August 2014
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
2
OBJECTIVES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period followed by a 
long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 20 of 77
Final v1.0
05 August 2014
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3
For Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes 
in days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0). 
Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 
3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
2.4
Safety Objectives – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done at the end of the optimization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(Stage 3).  For all subjects with a history of Crohn’s disease, an upper GI contrast series with 
small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 21 of 77
Final v1.0
05 August 2014
3
STUDY DESIGN
This will be an open-label, multicenter, 3-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stage 3).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. reduction and optimization 
period (if required); and a stabilization period that demonstrates stable PN/I.V. support for a 
minimum of 4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stage 3)
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2 and will include subjects who complete the main treatment period and who are willing to 
continue teduglutide treatment.  Subjects will continue to receive teduglutide 0.05 mg/kg/day SC 
for up to an additional 24 months or until teduglutide is commercially available, whichever 
comes earlier. (After the approval of marketing authorization, the study will continue as a 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 22 of 77
Final v1.0
05 August 2014
post-marketing clinical study to continuously provide teduglutide to the subjects until the product 
is commercially available.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 23 of 77
Final v1.0
05 August 2014
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V. 
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months or until 
Regulatory Approval
Stage 3


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 24 of 77
Final v1.0
05 August 2014
Schedules of evaluations for Stage 1, 2 and 3 can be found in Table 6-1, Table 6-2 and Table 6-3, 
respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization and treatment periods can 
be found in Appendix 1 and Appendix 2, respectively, and should be followed carefully 
throughout the study.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled during the recruitment period, 
which ends approximately 6 months after the initiation of the study.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1. Signed and dated Informed Consent Form (ICF) before any study-related procedures 
are performed
2. Men and women, 16 years of age or older at the time of signing the ICF 
3. Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/I.V. dependency prior to signature of ICF
4. For subjects with a history of Crohn’s disease, the subject should be in clinical 
remission for at least 12 weeks prior to dosing as demonstrated by clinical 
assessment, which may include procedure-based evidence of remission.
5. PN/I.V. requirement of at least 3 times per week during the week before screening 
and during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6. Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the 
start of teduglutide treatment, based upon the opinion of the investigator and approval 
by the sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b. Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time subject is 
optimized and enters stabilization
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 25 of 77
Final v1.0
05 August 2014
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 of this study:
1. Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1. Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or 
concurrent participation in any clinical study using an experimental drug that would 
affect the safety of teduglutide
2. Previous use of native GLP-2 or human growth hormone within 6 months prior to 
screening
3. Previous use of intravenous glutamine, octreotide, GLP-1 analog , or dipeptidyl 
peptidase-IV inhibitors within 30 days prior to screening
4. Previous use of teduglutide
5. Serial transverse enteroplasty or any other bowel lengthening procedure performed 
within the past 3 months
6. Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed 
during the 6 months prior to screening
7. Subjects with inflammatory bowel disease who require chronic systemic 
immunosuppressant therapy that was introduced or changed during the last 3 months
8. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9. Radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening
11. Major GI surgical intervention within 3 months prior to screening (insertion of 
feeding tube or endoscopic procedure is allowed)
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell 
carcinoma within 5 years
14. Active clinically significant pancreatic or biliary disease


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 26 of 77
Final v1.0
05 August 2014
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, 
bowel obstruction, severe water-electrolyte disturbances) within12 months prior to 
screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b. Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function:
a.
Serum creatinine ≥2 times ULN
b. Creatinine clearance < 50 mL/minute
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results 
including:
a.
Serum amylase level ≥2 times ULN
b. Serum lipase level ≥2 times ULN
20. Pregnant or lactating women
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years 
or older and/or at least 2 years had elapsed since her last menses) or who are not 
using medically acceptable methods of birth control during and for 30 days after the 
treatment period
22. Not capable of understanding or not willing to adhere to the study visit schedule and 
other protocol requirements
23. Evidence of untreated intestinal obstruction or active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevented completion of the study, or interfered with analysis of the study 
results
25. Presence of any of the excluded disease states described in Table 4-1.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 27 of 77
Final v1.0
05 August 2014
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue 
due to radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the 
last 3 months
Crohn’s disease or other diseases that require biological therapy (eg, 
anti-tumor necrosis factor or natalizumab) that was introduced or 
changed in the last 6 months
Untreated known pre-malignant or malignant change in upper or 
lower GI biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile 
polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada syndrome, 
Eversmeyerous polypius)
Intestinal or other major surgery scheduled within the time frame of 
the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency 
syndrome, severe combined immunodeficiency), hypersensitivity or 
allergies to teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or 
central nervous system)


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 28 of 77
Final v1.0
05 August 2014
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 
procedures described in Section 6.2.1.2.  As far as possible, all examinations scheduled for the 
end-of-study evaluations must be performed on all subjects who participate, but do not complete 
the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere with 
analysis of the study results (ie, compromise PN/I.V.):
      o Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that would put
the subject at any undue risk or prevent completion of the study
o Major surgical interventions (eg, abdominal, vascular)
o Crohn’s disease flare up
o Use of any excluded medication
o Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/ Sponsor decision (ie. subject non-compliance with study procedures)


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 29 of 77
Final v1.0
05 August 2014

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of NPS. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.
5
TREATMENTS AND TREATMENT PLAN
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the dosing period is in
Appendix 2.
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2.  In Stage 3, subjects can continue teduglutide treatment if deemed appropriate by the 
investigator.  During the extension, the PN/I.V. dosage will be adjusted as described in 
Appendix 3.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 24 months or 
until regulatory approval and commercial availability of teduglutide in Japan.  (After the 
approval of marketing authorization, the study will continue as a post-marketing clinical study 
until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during Stage 2 or 3) will continue to receive teduglutide treatment.  If 
a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 30 of 77
Final v1.0
05 August 2014
5.1
Treatments Administered 
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen.
5.1.1
Identification of Investigational Product 
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.
Active ingredient:
teduglutide
Added ingredients:
L-histidine, mannitol, monobasic and dibasic sodium 
phosphate
Route of administration:
SC injection
Dose:
0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and ICCC name and address. All medication supplied to be used in this study will be 
manufactured, tested, labeled, and released according to current legal requirements and Good 
Manufacturing Practice.  Ancillary supply kits containing the following will also be provided 
with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution

Syringes with needles for injection (dosing)

Alcohol swabs


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 31 of 77
Final v1.0
05 August 2014
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 32 of 77
Final v1.0
05 August 2014
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets (Appendix 4) and the study reference manual. Each 
day, the injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.
Dosing must be performed at least 14 hours prior to antibody testing, which will be performed at 
baseline and at Weeks 12 and 24 during Period 2 and at Months 6, 12, and 24 during Period 3. 
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues. 
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive
teduglutide treatment.  A subject will be considered to have achieved independence from PN/I.V. 
(completely weaned off PN) if the investigator prescribes no PN and there is no use of PN 
recorded in the subject diary at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 33 of 77
Final v1.0
05 August 2014
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded in the appropriate sections of the CRF.
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, coumadin, psychotropics, and digoxin), so consideration should be 
given to modifying concomitant medication regimens.  Down-titration of concomitant 
medication dosages should be considered when drugs, including those with a narrow therapeutic 
range, are given, especially if given at dosages that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stage 3) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 and 3 of this study are given in 
Appendix 2 and Appendix 3, respectively.
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 34 of 77
Final v1.0
05 August 2014

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes in 
days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms 

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP.  Samples for antibody analysis will be drawn at the start 
of treatment and at the EOT visit (prior to the administration of teduglutide and at least 
14 hours after the previous dose).  A 6-month follow-up is planned for any subjects testing 
positive for teduglutide-specific antibodies following the last dose of study drug.

Changes in urine output (48-hour oral fluid intake/urine output)

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 35 of 77
Final v1.0
05 August 2014
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 36 of 77
Final v1.0
05 August 2014
Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form.  This information will be shared 
with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF through the last dose of study drug.  Adverse events that are not resolved at 
the end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility 

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 37 of 77
Final v1.0
05 August 2014
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s 
medical history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form.  An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug will be captured and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 38 of 77
Final v1.0
05 August 2014
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
enter the SAE information into the SAE reporting system and fax supplemental data (eg, medical 
records or laboratory values, if applicable) to the sponsor. This ensures timely reporting of 
applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
The sponsor or designee will provide a FAX cover sheet for the investigators in the study 
reference manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 39 of 77
Final v1.0
05 August 2014
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect study 
product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related) 

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the study reference manual.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not reported in the clinical safety section of the Investigator Brochure (IB) or if the event is of 
greater frequency, specificity, or severity than is mentioned in the IB.  The investigator will 
receive a copy of the current valid version of the IB prior to the start of the study; however, the 
investigator will not be required to assess expectedness, nor should expectedness impact the 
investigator reporting SAEs within the timeframe herein defined.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 40 of 77
Final v1.0
05 August 2014
Upon receiving such notices, the investigator must review and retain the notice.  If it is 
determined that there is an unanticipated signal, the NPS SMT will analyze the data and prepare 
a summary supporting the determination and interpretation of the findings.  The sponsor or 
designee will send this summary to the investigators with instructions to provide it to their
Institutional Review Board (IRB).
The investigator should also comply with the IRB procedures for reporting any other safety 
information (ie, autopsy reports).  
NPS Pharmaceuticals, Inc. or its designee will be responsible for submitting SUSAR reports to 
the appropriate health authorities.  These reports will be submitted within the expedited
timeframe.
6.2.3
Pregnancy Reporting
In the event a subject becomes pregnant during the study, study drug will be discontinued and an 
SAE form will be completed to capture potential drug exposure during pregnancy. This will be 
reported within 24 hours of becoming aware of the pregnancy. The subject will be followed up 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
[miscarriage], voluntary abortion, or therapeutic abortion). If a pregnant subject also experiences 
an SAE, an additional SAE form will be completed and submitted within 24 hours as discussed 
above. 
In the event a female partner of a male subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator (PI) and a supplemental SAE form will be completed to 
capture the event.
6.2.4
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
A central laboratory will process all samples. 
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs, if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 41 of 77
Final v1.0
05 August 2014
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2 and Table 6-3.
Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 
Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; bicarbonate; total, direct, and indirect 
bilirubin; blood urea nitrogen; calcium; chloride; cholesterol; C-reactive protein; creatinine; 
creatinine clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; 
potassium; sodium; triglycerides; and uric acid
Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  
Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)
Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 or early termination during Stage 2 of the study, and at Months 6 and 12, 
and at the final visit or early termination in Stage 3.
If teduglutide-specific antibodies are detected, subjects may remain in study and will continue to 
be tested at each visit, as long as there are no concurrent AEs associated with immunogenicity.  
Subjects who test positive for teduglutide-specific antibodies at the end of Stage 2 will be 
allowed to enter Stage 3, as long as there are no concurrent AEs associated with 
immunogenicity.  The presence of teduglutide-specific antibodies will continue to be monitored 
at every visit until the end of this study.  If, at the final visit, the subject is still positive for 
teduglutide-specific antibodies, the subject will require follow-up blood draws as specified 
above. If any subject (previously negative for teduglutide antibodies) has specific 
anti-teduglutide antibodies at the final visit of this study, they will have follow-up blood draws 
for antibodies at Months 2, 3 and 6 post-study.  These may be done at a local laboratory
convenient to the subject, however all blood samples will be mailed to the central laboratory for 
analysis. If a subject’s results are negative at 2 successive visits within this time, follow-up may 
be terminated.  If at the end of 6 months the subject is still determined to have 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 42 of 77
Final v1.0
05 August 2014
teduglutide-specific antibodies, the PI and the sponsor will determine if additional follow-up 
may be required.  During this follow-up, subjects will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilence database.  Collection of AE 
and/or SAE information may be done via telephone contact. 
Teduglutide Concentrations
Teduglutide concentrations will be determined in the blood samples collected for antibody 
testing, ie, at baseline and at Weeks 12, 24 or early termination during Stage 2 of the study, and 
at Months 6, 12, and at the final visit or early termination in Stage 3.
6.2.5
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2 and Table 6-3).  If peripheral venous access 
is not possible, blood samples for citrulline may be drawn from a central line.  The samples will 
be processed according to instructions in the laboratory manual.
6.2.6
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.7
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 
Stages 1 and 2 and at the visits specified in Table 6-3 during Stage 3. The center staff will 
contact the subject at least 48 hours before the scheduled visits to remind the subject to start 
measuring complete I/O, and to record these measurements into the diary.  At these times of 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 43 of 77
Final v1.0
05 August 2014
48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at any required interim safety visit.
6.2.8
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 3 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.9
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
optimization and stabilization periods and the treatment periods in Stages 2 and 3 of the study.
6.2.10
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the PN/I.V. volume is adjusted as a result of a TEAE that 
is not related to study drug, then the diary data will not be included in the data analysis. If the 
subject has a TEAE that prevents him or her from adhering to study requirements, including PN 
adjustments, the subject may be withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 and 3 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.
6.2.11
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 44 of 77
Final v1.0
05 August 2014
6.2.12
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each visit and the details of any medications and changes therein (change in medication or 
dosage of medication) will be recorded on the CRF.
6.2.13
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and at the final visits of Stage 2 and Stage 3.  A brief examination of the GI and cardiovascular 
systems will be made at all other study visits.  Other body systems will be examined as clinically 
indicated.
6.2.14
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, and Table 6-3). Vital signs will include systolic and diastolic blood pressure 
(mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been sitting for 
5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded at the 
initial visits of Stages 1, 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.15
Electrocardiograms
A 12-lead ECG will be performed at Week 2 during Stage 1, at baseline, Week 4, and at the final 
visit during Stage 2, and at the first visit (last visit for Stage 2) and at Months 2 and 6 and the 
final visit during Stage 3.  The ECG will be done at the study center after the subject has been 
resting for at least 5 minutes.  Results will include general findings only (normal/abnormal).  
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 45 of 77
Final v1.0
05 August 2014
6.2.16
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1 , Table 6-2, and Table 6-3) for details and scheduling.
6.2.16.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2 and at the end of teduglutide 
exposure in Stage 3.  A colonoscopy is required at the beginning of the study, at the end of the 
main treatment period and at the end of the study to determine if any clinically significant 
changes have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a 
subject had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.
6.2.16.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0)
in Stage 2 of the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 
minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2

CL/F

V/F


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 46 of 77
Final v1.0
05 August 2014
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures – Stage 3, 
Table 6-3.
Subjects who drop out of the study prior to the final visit should have all end-of-study procedures 
done. 






Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 49 of 77
Final v1.0
05 August 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
Eligibility criteria
X
Crohn’s disease assessment
X
Physical examinationc
X
X
X
X
X
X
X
X
Evaluation of PN/I.V.
Xd
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Colonscopy/      
  Sigmoidoscopy
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
Xe
X
X
X
X
X
X
X
Height
X
X
12-lead ECG
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrulline
X
X
X
X
X
Teduglutide concentration 
and antibodies to 
teduglutide and E. coli
protein
X
X
X
PK sampling
Xi
(X)
(X)
(X)
(X)
(X)
Urine pregnancy test
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety evaluationf
[X]g
[X]
[X]
[X]
[X]
[X]
48-hour oral fluid intakeh
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputh
(Diary)
X
X
X
X
X
X
X
X
Diary
X
X
X
X
X
X
X
X
X
Teduglutide dosingj
X
X
X
X
X
X
X
X
X
Compliancek
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 50 of 77
Final v1.0
05 August 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
( X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous (volume); V = visit
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone.
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance.
c A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit.
d The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
e This is the second of 2 body weight measurements that will be used to determine drug volume.
f Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
g At the Visit 4/Week 2 interim safety visit, laboratory evaluations and 48-hour I/O are not required.  These will be assessed only if the PN/I.V. adjustment was 
tolerated.
h All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.
i Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7.
j Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will self-inject the study drug at home.
k Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 51 of 77
Final v1.0
05 August 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First Visita 
(last visit 
for Stage 2)
Mo 
1/13
Mo 
2/14
Mo
3/15
Mo 
4/16 
Mo 
5/17
Mo 
6/18
Mo 
7/19
Mo 
8/20
Mo 
9/21
Mo 
10/22
Mo 
11/23
Mo 
12
Final       
(Mo 24) 
(or early 
termination)
Visit Number:
V1
V2/
14
V3/ 
15
V4/ 
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/ 
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days)
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Eligibility, Informed consent
X
Medical history, 
demographics
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
Height
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
12-lead ECG
X
Xg
X
X
X
Colonoscopy/sigmoidoscopy 
of remnant colon
X
Citrulline
X
X
X
X
X
X
X 
X
Teduglutide concentration 
and antibodies to teduglutide
and E. coli protein
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety visitd
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Diary e
X
X
X
X
X
X
X
X
48-hour oral fluid intakef 
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputf
(Diary)
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 52 of 77
Final v1.0
05 August 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Evaluation of PN/I.V. (actual 
volume L/week)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
[X ] = Possible interim safety evaluation time point (Refer to footnote “d”.); ECG = electrocardiogram; Mo = month; PN/I.V. = parenteral nutrition/intravenous (support); V = visit
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the Month 2 visit.  Interim 
(standard of care) visits may be utilized to assess patients’ well-being (ie, occurrence of adverse events) and to check for any changes in medications.
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed appropriate.
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone.
c Full physical examination to be performed at first and final visit; a brief examination will be performed at all other study visits.
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  Hematocrit, serum blood urea 
nitrogen and serum creatinine, and urine sodium will be measured.
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The measurements should include 
1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily.
g An ECG will be taken at Visit 3, but not at Visit 15.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 53 of 77
Final v1.0
05 August 2014
7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s CRF by the investigational site 
staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case of 
computerized source data, the investigator has to give the sponsor access to the subject files at 
each monitoring visit. To ensure that data have been entered correctly on the CRF, they will be 
100% source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding any questions or discrepant data. The investigator or designee will be 
responsible for the timely recording of subject data into the CRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The PI or designee will review all CRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will sign the CRF via an electronic signature. The PI
will be responsible for reviewing the data in a timely manner.  Non-CRF data will be sent to the 
sponsor or designee via a data transfer from the appropriate vendor for assimilation into the 
database. Paper copies non-CRF data will be signed and dated by the investigator and filed.
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with CRF guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that should 
be resolved at the study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 54 of 77
Final v1.0
05 August 2014
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.
An audit will be performed by the Data Management group. When all issues from the audit are 
resolved, and all data management processes are completed for finalizing the database, the 
database will be ready for statistical analysis by NPS or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC. In the event that the appropriate individual at the site provides an 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 55 of 77
Final v1.0
05 August 2014
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.
8
STATISTICAL METHODOLOGY 
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 56 of 77
Final v1.0
05 August 2014

Change in days per week of PN/I.V. support

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the LS mean percent change in weekly 
PN/I.V. volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the 
placebo group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, 
PN/I.V. results will be compared with those from Study CL0600-020.  The comparison 
should take into account the anticipated variability of the data due to the small number of 
subjects in Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95%
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with those 
from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should take 
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 57 of 77
Final v1.0
05 August 2014
8.2.2
Efficacy and Pharmacodynamics – Stage 3
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.
8.3
Safety – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, laboratory safety data, antibodies to teduglutide, and changes in urine 
output, body weight, and BMI.  See Section 6.2 for a full list of safety variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg., number and percentage of subjects) for each treatment group. Adverse 
events will be summarized by severity, relationship to treatment, AEs leading to discontinuation, 
and AEs leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point for each treatment group. 
The number and percentage of subjects classified as having antibodies to teduglutide will be used to 
summarize the presence of antibodies for each treatment group.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study. 
The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow up. The primary population analyzed for 
efficacy will be the ITT population. An additional per-protocol population analysis will also be 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 58 of 77
Final v1.0
05 August 2014
performed as secondary/sensitivity analysis. Detailed per-protocol evaluable definitions will be 
documented in the Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 59 of 77
Final v1.0
05 August 2014
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
NPS SMT has assessed it as an unanticipated problem.  Approval for protocol amendments will 
be transmitted in writing to the investigator.
The investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed one year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject. A subject information/ICF model will be provided by the 
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 60 of 77
Final v1.0
05 August 2014
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods. The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial. IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 61 of 77
Final v1.0
05 August 2014
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 62 of 77
Final v1.0
05 August 2014
10
REFERENCES
None


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 63 of 77
Final v1.0
05 August 2014
APPENDIX 1:
PN/I.V. OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 64 of 77
Final v1.0
05 August 2014
by targeted urine output of 1.0-2.0 L/day.  If a subject has not achieved an optimal tolerated 
volume of PN/I.V. after 8 weeks, consult the NPS Medical Director.
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 65 of 77
Final v1.0
05 August 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to 
reduce volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Monitor.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 66 of 77
Final v1.0
05 August 2014
Table A2-1: PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% (Week 2) or to 
previous level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A2-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of stabilized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Table A2-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 
PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be collected to 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 67 of 77
Final v1.0
05 August 2014
evaluate hydration and nutrition (see Table A2-2).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. (Reduction 
of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
Table A2- 3: Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is 
dehydrated (See Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not 
dehydrated, but is inadequately nourished 
(See Table A2-2)
If possible, maintain PN/I.V. volume 
and increase nutrition. If not, increase 
PN/I.V. to previous volumea
Baseline output or greater and subject is 
adequately hydrated and nourished (See 
Table A2-2)
Maintain PN/I.V.
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate increase in PN/I.V.
is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V..
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 68 of 77
Final v1.0
05 August 2014
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  During the 
remainder of the study, subjects may undergo 1 additional attempt to reduce volume by 
at least 10%.
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 69 of 77
Final v1.0
05 August 2014
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of OPTIMIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Director.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 70 of 77
Final v1.0
05 August 2014
Table A3- 1: PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% or to previous 
level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A1-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of optimized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily.  All blood and urine samples should be taken at a consistent time period throughout 
the study, convenient for the subject and site staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed after 5 to 7 days of the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. Depending on the 
wellbeing of the subject it is at the discretion of the investigator to abstain from the 
laboratory safety samples.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 71 of 77
Final v1.0
05 August 2014
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.
Table A3-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
* AND consistent with subject’s previous levels prior to study entry.
BUN = blood urea nitrogen; ULN = upper limit of normal
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 72 of 77
Final v1.0
05 August 2014
A. STUDY ORGANIZATION
Sponsor:
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
Medical Monitor (Medical expert of the sponsor):
, MD
, Clinical Development-GI
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
Telephone: 
Study statistician:
, MS
, SAS Programming & Biostatistics
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
Data manager:
, Data Management
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 73 of 77
Final v1.0
05 August 2014
Pharmacovigilance:
, RPh, PhD
, Pharmacovigilance
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
CONTRACT RESEARCH ORGANIZATIONS:
In-Country Clinical Caretaker:
(Contact: 
, Pharmaceutical Development Project Division, Regulatory Affairs 
Department, Regulatory Affairs and Application Group, 
)
EPS Associate Co., Ltd.
2-1-3, Korau, Bunkyo-ku,
Tokyo 112-0004, Japan
TEL:
 FAX:
Emergency contacts:
TEL: 
TEL: 
EPS Associates Co., Ltd.
2-1-3 Koraku, Bunkyo-ku
Tokyo 112-0004, Japan
Coordinating investigator:
 MD, PhD 
, Japan


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 74 of 77
Final v1.0
05 August 2014
B. LIST OF PRINCIPAL INVESTIGATORS AND INVESTIGATIONAL SITES
Investigational Sites
Investigators 
 Japan 
TEL:
 
Japan
TEL:
 
 Japan
TEL: 
 
 
 Japan
TEL: 
 
 Japan
TEL: 


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 75 of 77
Final v1.0
05 August 2014
C. LIST OF CLINICAL RESEARCH ASSOCIATES
, 
EPS Associates Co., Ltd.
2-1-3, Korau, Bunkyo-ku,
Tokyo 112-0004, Japan


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 76 of 77
Final v1.0
05 August 2014
D. DURATION OF THE STUDY
The proposed duration of the study is from 2014 through 2016.  Study start is defined as first 
patient screened; study end is defined as the hard-lock of the database.


Protocol TED-C14-004
Gattex® (teduglutide [rDNA origin]) for injection
Page 77 of 77
Final v1.0
05 August 2014
E.  PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study 
in compliance with this protocol, any future amendments, and with any other study conduct procedures 
provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practice 
(GCP) and all other applicable regulatory requirements to obtain written and dated approval from the 
Institutional or Central Review Board (IRB) or Independent Ethics Committee (IRB) for the study 
protocol and any amendments thereof, written informed consent or updates thereof, subject recruitment 
procedures (eg, advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from the 
sponsor and review and documented approval from the IRB, except to eliminate an immediate hazard to 
the study subjects, or when change(s) involves only logistical or administrative aspects of the clinical 
study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by 
the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in 
this protocol, and any other information provided by the sponsor or In-country Clinical Caretaker 
including, but not limited to, the current Investigator’s Brochure or equivalent document and approved 
product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the foreseen 
duration of the clinical study in order to conduct the study properly, ethically, and safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


TEDUGLUTIDE (ALX-0600)
A 3-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 2.0
Phase 3
Sponsor:  NPS Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
USA
Medical Monitor (Medical Expert of the Sponsor):
 MD
 Clinical Development
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-23 Shimomiyabicho, Shinjuku-ku,
Tokyo 162-0822, Japan
TEL:
FAX:
Protocol v1.0:
05 August 2014
Protocol v2.0, Amendment 1:
20 August 2014 (administrative amendment)
The information contained in this document is the property of NPS Pharmaceuticals, Inc. It is 
understood that the information will not be disclosed to others aside from the investigator(s) and duly 
designated staff, applicable IRB(s) and regulatory authorities without prior written approval from NPS 
Pharmaceuticals Inc., except to the extent necessary to obtain informed consent from those persons to 
whom the study drug may be administered.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 2 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
SUMMARY
Protocol TED-C14-004
Title of Study: A 3-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 3-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous volume (PN/I.V.) support optimization period; and a 
stabilization period in which stable administration of PN/I.V. support, defined as a targeted 
urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and nourished,
is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a subject fails to 
remain stable for at least 4 consecutive weeks, the subject may start the optimization period 
again, beginning with Visit 1.1. Those subjects who fail to stabilize after 2 attempts will not 
proceed further and will not be dosed. Stage 2 will be a dosing period of 24 weeks, during 
which subjects will self-administer the study drug at home.
Stage 3 is the long-term extension portion of the study, which will begin immediately 
following Stage 2.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 
24 months or until regulatory approval and commercial availability of teduglutide in Japan. 
(After the approval of marketing authorization, the study will continue as a post-marketing 
clinical study until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled during the recruitment 
period, which ends approximately 6 months after the initiation of the study.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 3 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:
o
Actual PN/I.V. usage matches prescribed PN/I.V.
o
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.
o
Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function: 
o
Total bilirubin < 2 times upper limit of normal (ULN)
o
Aspartate aminotransferase (AST) < 5 times ULN
o
Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function:
o
Serum creatinine < 2 times ULN
o
Creatinine clearance ≥50 mL/minute

Adequate pancreatic function:
o
Serum amylase < 2 times ULN
o
Serum lipase < 2 times ULN


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 4 of 72
Final v2.0, Administrative Amendment 1
20 August 2014

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC)
injection is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile 
water for injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study.
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen or either thigh or arm. The first SC injection should be administered under the 
supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period; and a stabilization period that demonstrates stable administration 
of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks (total maximum
16 weeks for optimization/stabilization periods).  Subjects who fail optimization may repeat 
this period (taking up to an additional 16 weeks).  Therefore the total possible duration of 
Stage 1 is up to 33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue in the extension 
treatment period for up to an additional 24 months (Stage 3) or until teduglutide is 
commercially available, whichever comes first. (After the approval of marketing 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 5 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
authorization, the study will continue as a post-marketing clinical study in order to 
continuously provide teduglutide to the subjects until the product is commercially available).
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stage 3:  Absolute and percent change from baseline in 
weekly PN/I.V. volume and changes in days per week of PN/I.V. support and plasma 
citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose pharmacokinetics will be evaluated on the 
first day of teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected 
pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
Safety – All Stages:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, 
laboratory safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 6 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
changes in urine output (48-hour I/O), body weight and body mass index (BMI) will be 
evaluated.  An abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will 
be done at the end of the optimization period if these procedures were not done in the 
6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated at the end of the 
main treatment period (Stage 2) and at the end of the extension treatment period (Stage 3).  
For all subjects with a history of Crohn’s disease, an upper gastrointestinal (GI) contrast series 
with small bowel follow through will be performed during the stabilization period, prior to the 
baseline visit.
Statistical methods:  No formal testing will be conducted for efficacy variables.  For 
continuous variables, descriptive statistics will be used to summarize median, maximum, 
minimum, mean (± standard deviation [SD]), geometric mean (± standard error [SE]) and its 
95% confidence interval.  For categorical variables, n (%) will be summarized. Individual 
data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the 
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 8 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Reviewed:
 
 Japan


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 9 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................1
SUMMARY ....................................................................................................................................2
SIGNATURE PAGE......................................................................................................................7
TABLE OF CONTENTS ..............................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................14
1
INTRODUCTION..................................................................................................................16
1.1
Background.....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design.............................................................................................19
2
OBJECTIVES ........................................................................................................................19
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2 ....................................................19
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3 ....................................................20
2.3
Pharmacokinetic Endpoints – Stage 2 Only....................................................................20
2.4
Safety Objectives – All Stages........................................................................................20
3
STUDY DESIGN....................................................................................................................21
3.1
Main Treatment Period (Stages 1 and 2) ........................................................................21
3.2
Extension Treatment Period (Stage 3)............................................................................21
4
SUBJECT SELECTION AND PARTICIPATION............................................................24
4.1
Number of Subjects.........................................................................................................24
4.2
Inclusion Criteria ............................................................................................................24
4.2.1
Inclusion in Stage 3..........................................................................................25
4.3
Exclusion Criteria ...........................................................................................................25
4.4
Subject Withdrawal Criteria ...........................................................................................28
4.4.1
Events Necessitating Withdrawal from Study.................................................28
4.4.2
Re-screening of Subjects..................................................................................29
5
TREATMENTS AND TREATMENT PLAN .....................................................................29
5.1
Treatments Administered................................................................................................30
5.1.1
Identification of Investigational Product .........................................................30


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 10 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
5.1.2
Packaging and Labeling...................................................................................30
5.1.3
Storage, Accountability, and Stability.............................................................31
5.2
Dose Regimen.................................................................................................................31
5.2.1
Selection of Doses in Study.............................................................................31
5.2.2
Selection and Timing of Dose for Each Subject..............................................32
5.2.3
Subjects Who Achieve PN/I.V. Independence ................................................32
5.2.4
Compliance with Dosing Regimens.................................................................33
5.3
Prior and Concomitant Medications ...............................................................................33
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................33
6.1
Efficacy Evaluations.......................................................................................................33
6.2
Safety Evaluations ..........................................................................................................34
6.2.1
Adverse Events ................................................................................................34
6.2.2
Serious Adverse Events ...................................................................................37
6.2.3
Pregnancy Reporting........................................................................................40
6.2.4
Laboratory Evaluations....................................................................................40
6.2.5
Plasma Citrulline..............................................................................................42
6.2.6
Women of Child Bearing Potential..................................................................42
6.2.7
48-Hour Oral Fluid Intake and Urine Output ..................................................42
6.2.8
Clinical Assessment of Crohn’s Disease Activity ...........................................43
6.2.9
Subject Diaries.................................................................................................43
6.2.10
Changes in PN/I.V. Volume ............................................................................43
6.2.11
Medical History and Demographics ................................................................43
6.2.12
Concomitant Medication Assessment..............................................................44
6.2.13
Physical Examinations.....................................................................................44
6.2.14
Vital Signs and Body Weight ..........................................................................44
6.2.15
Electrocardiograms ..........................................................................................44
6.2.16
Gastrointestinal-specific Testing .....................................................................45
6.3
Pharmacokinetic Evaluations..........................................................................................45
6.4
Schedule of Evaluations and Procedures........................................................................46
7
DATA MANAGEMENT.......................................................................................................53
7.1
Data Collection ...............................................................................................................53
7.2
Record Retention ............................................................................................................54


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 11 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
7.3
Quality Control ...............................................................................................................54
8
STATISTICAL METHODOLOGY.....................................................................................55
8.1
Demographic and Baseline Variables.............................................................................55
8.2
Efficacy and Pharmacodynamic Variables .....................................................................55
8.2.1
Efficacy and Pharmacodynamics – Stage 2.....................................................55
8.2.2
Efficacy and Pharmacodynamics – Stage 3.....................................................57
8.3
Safety – All Stages..........................................................................................................57
8.3.1
Statistical Methods for Safety Variables..........................................................57
8.4
Pharmacokinetic Variables – Stage 2 Only ....................................................................57
8.5
Analysis Populations, Data Sets, and Time Points .........................................................57
8.5.1
Analysis Populations........................................................................................57
8.6
Statistical/Analytical Issues ............................................................................................58
8.6.1
Adjustments for Covariates..............................................................................58
8.6.2
Handling of Dropouts or Missing Data............................................................58
8.6.3
Interim Analyses ..............................................................................................58
8.6.4
Multiple Comparisons/Multiplicity .................................................................58
8.6.5
Use of an Efficacy Subset of Subjects.............................................................58
8.6.6
Examination of Subgroups...............................................................................58
8.7
Determination of Sample Size ........................................................................................58
8.8
Changes to Planned Statistical Analyses ........................................................................59
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................59
9.1
Declaration of Helsinki and Ethical Review...................................................................59
9.2
Subject Information and Consent....................................................................................59
9.3
Subject Data Protection...................................................................................................60
9.4
Payment and Compensation............................................................................................60
9.5
Changes to the Protocol ..................................................................................................60
9.6
Confidentiality/Publication of the Study ........................................................................61
9.7
Study Termination ..........................................................................................................61
10 REFERENCES.......................................................................................................................62
APPENDIX 1:
PN/I.V. OPTIMIZATION.............................................................................63


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 12 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2).............................................................................................................65
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3) .................................................................................69
APPENDIX 4:  PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE......72




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 14 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NPS
NPS Pharmaceuticals, Inc.
PI
Principal Investigator
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 15 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
PN/I.V.
Parenteral Nutrition/Intravenous (volume)
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SMT
Safety Management Team
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 16 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
1
INTRODUCTION
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 17 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats. In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 18 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.
Clinical Studies
Results of the pivotal study filed for the US New Drug Application, CL0600-020, showed that 
teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing 
parenteral nutrition/intravenous (PN/I.V.) volume in adult subjects with SBS.  In this study the 
responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects achieving a 
mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and in the United States (US).  The clinical 
profile and issues related to SBS and PN/I.V. in Japan are similar to those in the EU and in the 
US.    Therefore, there is an unmet medical need for Japanese patients with PN-dependent SBS.  
This study is designed to provide evidence of safety and efficacy of teduglutide in a Japanese 
SBS patient population. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 19 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
2
OBJECTIVES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period followed by a 
long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 20 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3
For Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes 
in days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0). 
Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 
3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
2.4
Safety Objectives – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done at the end of the optimization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(Stage 3).  For all subjects with a history of Crohn’s disease, an upper GI contrast series with 
small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 21 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
3
STUDY DESIGN
This will be an open-label, multicenter, 3-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stage 3).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. reduction and optimization 
period (if required); and a stabilization period that demonstrates stable PN/I.V. support for a 
minimum of 4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stage 3)
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2 and will include subjects who complete the main treatment period and who are willing to 
continue teduglutide treatment.  Subjects will continue to receive teduglutide 0.05 mg/kg/day SC 
for up to an additional 24 months or until teduglutide is commercially available, whichever 
comes earlier. (After the approval of marketing authorization, the study will continue as a 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 22 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
post-marketing clinical study to continuously provide teduglutide to the subjects until the product 
is commercially available.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 23 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V. 
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months or until 
Regulatory Approval
Stage 3


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 24 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Schedules of evaluations for Stage 1, 2 and 3 can be found in Table 6-1, Table 6-2 and Table 6-3, 
respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization and treatment periods can 
be found in Appendix 1 and Appendix 2, respectively, and should be followed carefully 
throughout the study.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled during the recruitment period, 
which ends approximately 6 months after the initiation of the study.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1. Signed and dated Informed Consent Form (ICF) before any study-related procedures 
are performed
2. Men and women, 16 years of age or older at the time of signing the ICF 
3. Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/I.V. dependency prior to signature of ICF
4. For subjects with a history of Crohn’s disease, the subject should be in clinical 
remission for at least 12 weeks prior to dosing as demonstrated by clinical 
assessment, which may include procedure-based evidence of remission.
5. PN/I.V. requirement of at least 3 times per week during the week before screening 
and during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6. Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the 
start of teduglutide treatment, based upon the opinion of the investigator and approval 
by the sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b. Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time subject is 
optimized and enters stabilization
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 25 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 of this study:
1. Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1. Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or 
concurrent participation in any clinical study using an experimental drug that would 
affect the safety of teduglutide
2. Previous use of native GLP-2 or human growth hormone within 6 months prior to 
screening
3. Previous use of intravenous glutamine, octreotide, GLP-1 analog , or dipeptidyl 
peptidase-IV inhibitors within 30 days prior to screening
4. Previous use of teduglutide
5. Serial transverse enteroplasty or any other bowel lengthening procedure performed 
within the past 3 months
6. Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed 
during the 6 months prior to screening
7. Subjects with inflammatory bowel disease who require chronic systemic 
immunosuppressant therapy that was introduced or changed during the last 3 months
8. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9. Radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening
11. Major GI surgical intervention within 3 months prior to screening (insertion of 
feeding tube or endoscopic procedure is allowed)
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell 
carcinoma within 5 years
14. Active clinically significant pancreatic or biliary disease


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 26 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, 
bowel obstruction, severe water-electrolyte disturbances) within12 months prior to 
screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b. Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function:
a.
Serum creatinine ≥2 times ULN
b. Creatinine clearance < 50 mL/minute
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results 
including:
a.
Serum amylase level ≥2 times ULN
b. Serum lipase level ≥2 times ULN
20. Pregnant or lactating women
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years 
or older and/or at least 2 years had elapsed since her last menses) or who are not 
using medically acceptable methods of birth control during and for 30 days after the 
treatment period
22. Not capable of understanding or not willing to adhere to the study visit schedule and 
other protocol requirements
23. Evidence of untreated intestinal obstruction or active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevented completion of the study, or interfered with analysis of the study 
results
25. Presence of any of the excluded disease states described in Table 4-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 27 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue 
due to radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the 
last 3 months
Crohn’s disease or other diseases that require biological therapy (eg, 
anti-tumor necrosis factor or natalizumab) that was introduced or 
changed in the last 6 months
Untreated known pre-malignant or malignant change in upper or 
lower GI biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile 
polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada syndrome, 
Eversmeyerous polypius)
Intestinal or other major surgery scheduled within the time frame of 
the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency 
syndrome, severe combined immunodeficiency), hypersensitivity or 
allergies to teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or 
central nervous system)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 28 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 
procedures described in Section 6.2.1.2. As far as possible, all examinations scheduled for the 
end-of-study evaluations must be performed on all subjects who participate, but do not complete 
the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere with 
analysis of the study results (ie, compromise PN/I.V.):
      o Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that would put
the subject at any undue risk or prevent completion of the study
o Major surgical interventions (eg, abdominal, vascular)
o Crohn’s disease flare up
o Use of any excluded medication
o Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/ Sponsor decision (ie. subject non-compliance with study procedures)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 29 of 72
Final v2.0, Administrative Amendment 1
20 August 2014

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of NPS. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.
5
TREATMENTS AND TREATMENT PLAN
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the dosing period is in
Appendix 2.
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2.  In Stage 3, subjects can continue teduglutide treatment if deemed appropriate by the 
investigator.  During the extension, the PN/I.V. dosage will be adjusted as described in 
Appendix 3.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 24 months or 
until regulatory approval and commercial availability of teduglutide in Japan.  (After the 
approval of marketing authorization, the study will continue as a post-marketing clinical study 
until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during Stage 2 or 3) will continue to receive teduglutide treatment.  If 
a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 30 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
5.1
Treatments Administered 
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen.
5.1.1
Identification of Investigational Product 
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.
Active ingredient:
teduglutide
Added ingredients:
L-histidine, mannitol, monobasic and dibasic sodium 
phosphate
Route of administration:
SC injection
Dose:
0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and ICCC name and address. All medication supplied to be used in this study will be 
manufactured, tested, labeled, and released according to current legal requirements and Good 
Manufacturing Practice.  Ancillary supply kits containing the following will also be provided 
with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution

Syringes with needles for injection (dosing)

Alcohol swabs


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 31 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 32 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets and the study reference manual. Each day, the 
injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.
Dosing must be performed at least 14 hours prior to antibody testing, which will be performed at 
baseline and at Weeks 12 and 24 during Period 2 and at Months 6, 12, and 24 during Period 3. 
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues. 
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive
teduglutide treatment.  A subject will be considered to have achieved independence from PN/I.V. 
(completely weaned off PN) if the investigator prescribes no PN and there is no use of PN 
recorded in the subject diary at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 33 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded in the appropriate sections of the CRF.
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, coumadin, psychotropics, and digoxin), so consideration should be 
given to modifying concomitant medication regimens.  Down-titration of concomitant 
medication dosages should be considered when drugs, including those with a narrow therapeutic 
range, are given, especially if given at dosages that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stage 3) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 and 3 of this study are given in 
Appendix 2 and Appendix 3, respectively.
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 34 of 72
Final v2.0, Administrative Amendment 1
20 August 2014

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes in 
days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms 

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP.  Samples for antibody analysis will be drawn at the start 
of treatment and at the EOT visit (prior to the administration of teduglutide and at least 
14 hours after the previous dose).  A 6-month follow-up is planned for any subjects testing 
positive for teduglutide-specific antibodies following the last dose of study drug.

Changes in urine output (48-hour oral fluid intake/urine output)

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 35 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 36 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form.  This information will be shared 
with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF through the last dose of study drug.  Adverse events that are not resolved at 
the end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility 

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 37 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s 
medical history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form.  An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug will be captured and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 38 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
enter the SAE information into the SAE reporting system and fax supplemental data (eg, medical 
records or laboratory values, if applicable) to the sponsor. This ensures timely reporting of 
applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
The sponsor or designee will provide a FAX cover sheet for the investigators in the study 
reference manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 39 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect study 
product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related) 

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the study reference manual.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not reported in the clinical safety section of the Investigator Brochure (IB) or if the event is of 
greater frequency, specificity, or severity than is mentioned in the IB.  The investigator will 
receive a copy of the current valid version of the IB prior to the start of the study; however, the 
investigator will not be required to assess expectedness, nor should expectedness impact the 
investigator reporting SAEs within the timeframe herein defined.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 40 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Upon receiving such notices, the investigator must review and retain the notice.  If it is 
determined that there is an unanticipated signal, the NPS SMT will analyze the data and prepare 
a summary supporting the determination and interpretation of the findings.  The sponsor or 
designee will send this summary to the investigators with instructions to provide it to their
Institutional Review Board (IRB).
The investigator should also comply with the IRB procedures for reporting any other safety 
information (ie, autopsy reports).  
NPS Pharmaceuticals, Inc. or its designee will be responsible for submitting SUSAR reports to 
the appropriate health authorities.  These reports will be submitted within the expedited
timeframe.
6.2.3
Pregnancy Reporting
In the event a subject becomes pregnant during the study, study drug will be discontinued and an 
SAE form will be completed to capture potential drug exposure during pregnancy. This will be 
reported within 24 hours of becoming aware of the pregnancy. The subject will be followed up 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
[miscarriage], voluntary abortion, or therapeutic abortion). If a pregnant subject also experiences 
an SAE, an additional SAE form will be completed and submitted within 24 hours as discussed 
above. 
In the event a female partner of a male subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator (PI) and a supplemental SAE form will be completed to 
capture the event.
6.2.4
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
The site’s clinical laboratory will centrifuge and send the samples to the central lab, SRL 
Medisearch Inc. SRL Medisearch will analyze those specimens while sending the citrulline、
antibody, and PK samples to NPS headquarters in the U.S.
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs, if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 41 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2 and Table 6-3.
Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 
Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; total, direct, and indirect bilirubin; blood 
urea nitrogen; calcium; chloride; total-cholesterol; C-reactive protein; creatinine; creatinine 
clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; potassium; 
sodium; triglycerides; and uric acid
Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  
Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)
Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 or early termination during Stage 2 of the study, and at Months 6 and 12, 
and at the final visit or early termination in Stage 3.
If teduglutide-specific antibodies are detected, subjects may remain in study and will continue to 
be tested at each visit, as long as there are no concurrent AEs associated with immunogenicity.  
Subjects who test positive for teduglutide-specific antibodies at the end of Stage 2 will be 
allowed to enter Stage 3, as long as there are no concurrent AEs associated with 
immunogenicity.  The presence of teduglutide-specific antibodies will continue to be monitored 
at every visit until the end of this study.  If, at the final visit, the subject is still positive for 
teduglutide-specific antibodies, the subject will require follow-up blood draws as specified 
above. If any subject (previously negative for teduglutide antibodies) has specific 
anti-teduglutide antibodies at the final visit of this study, they will have follow-up blood draws 
for antibodies at Months 2, 3 and 6 post-study.  These may be done at a local laboratory
convenient to the subject, however all blood samples will be mailed to the central laboratory for 
analysis.  If a subject’s results are negative at 2 successive visits within this time, follow-up may 
be terminated.  If at the end of 6 months the subject is still determined to have 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 42 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
teduglutide-specific antibodies, the PI and the sponsor will determine if additional follow-up 
may be required.  During this follow-up, subjects will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilence database.  Collection of AE 
and/or SAE information may be done via telephone contact. 
Teduglutide Concentrations
Teduglutide concentrations will be determined in the blood samples collected for antibody 
testing, ie, at baseline and at Weeks 12, 24 or early termination during Stage 2 of the study, and 
at Months 6, 12, and at the final visit or early termination in Stage 3.
6.2.5
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2 and Table 6-3).  If peripheral venous access 
is not possible, blood samples for citrulline may be drawn from a central line.  The samples will 
be processed according to instructions in the laboratory manual.
6.2.6
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.7
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 
Stages 1 and 2 and at the visits specified in Table 6-3 during Stage 3. The center staff will 
contact the subject at least 48 hours before the scheduled visits to remind the subject to start 
measuring complete I/O, and to record these measurements into the diary.  At these times of 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 43 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at any required interim safety visit.
6.2.8
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 3 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.9
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
optimization and stabilization periods and the treatment periods in Stages 2 and 3 of the study.
6.2.10
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the PN/I.V. volume is adjusted as a result of a TEAE that 
is not related to study drug, then the diary data will not be included in the data analysis. If the 
subject has a TEAE that prevents him or her from adhering to study requirements, including PN 
adjustments, the subject may be withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 and 3 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.
6.2.11
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 44 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
6.2.12
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each visit and the details of any medications and changes therein (change in medication or 
dosage of medication) will be recorded on the CRF.
6.2.13
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and at the final visits of Stage 2 and Stage 3.  A brief examination of the GI and cardiovascular 
systems will be made at all other study visits.  Other body systems will be examined as clinically 
indicated.
6.2.14
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, and Table 6-3). Vital signs will include systolic and diastolic blood pressure 
(mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been sitting for 
5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded at the 
initial visits of Stages 1, 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.15
Electrocardiograms
A 12-lead ECG will be performed at Week 2 during Stage 1, at baseline, Week 4, and at the final 
visit during Stage 2, and at the first visit (last visit for Stage 2) and at Months 2 and 6 and the 
final visit during Stage 3.  The ECG will be done at the study center after the subject has been 
resting for at least 5 minutes.  Results will include general findings only (normal/abnormal).  
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 45 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
6.2.16
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1 , Table 6-2, and Table 6-3) for details and scheduling.
6.2.16.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2 and at the end of teduglutide 
exposure in Stage 3.  A colonoscopy is required at the beginning of the study, at the end of the 
main treatment period and at the end of the study to determine if any clinically significant 
changes have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a 
subject had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.
6.2.16.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0)
in Stage 2 of the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 
minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2

CL/F

V/F


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 46 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures – Stage 3, 
Table 6-3.
Subjects who drop out of the study prior to the final visit should have all end-of-study procedures 
done. 




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 48 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 6-1
Schedule of Evaluations and Procedures – Stage 1
Procedures
Prior to
screening
Screening
(7-day 
maximum)
PN/I.V. Optimization Period l
(8-week maximum)
PN/I.V. 
Stabilization 
Period
4-8 weeks 
(± 7 days)
Week 2
(± 3 days)
Week 4 
(± 3 days
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
[X ] = possible interim safety evaluation time point (Refer to footnote “i”.); BMI = body mass index; ECG = electrocardiogram; PN/I.V. = parenteral 
nutrition/intravenous (volume); V = visit
l One re-challenge of the optimization/stabilization is permitted
a ICF must be signed before the start of the 48-hour urine output measurements and any other study-related procedures.
b A full physical examination is to be performed at screening.
c PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
d Abdominal ultrasound should be completed during the stabilization period, prior to the baseline visit if not performed within 6 months prior to screening.
e Upper GI contrast series with small bowel follow-through is required for patients with Crohn’s disease.  This should be completed during the stabilization 
period, prior to the baseline visit.
f Colonoscopy/sigmoidoscopy of remnant colon with polyp removal before teduglutide exposure will be performed in patients with any colon remnant including 
rectal stump evaluation. Colonoscopy should be completed during the stabilization period, prior to the baseline visit, if required. If a subject had a normal 
colonoscopy/sigmoidoscopy within 6 months prior to screening, a baseline colonoscopy/sigmoidoscopy will not be required.
g At screening, information on all medications taken in the previous 30 days will be collected.
h This is the first of 2 body weight measurements that will be used to determine drug volume.
i Interim safety evaluations will be done 5 to 7 days after any scheduled visit where a PN/I.V. change was made.  These measures include 48-hour oral fluid
intake, 48-hour urine volume, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
j An interim safety evaluation should be conducted toward the end of the stabilization period to determine that the subject is compliant with Inclusion Criterion 6 
(stable PN/I.V.) and Exclusion Criteria 17 (hepatic function) and 18 (renal function).
k All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 49 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
Eligibility criteria
X
Crohn’s disease assessment
X
Physical examinationc
X
X
X
X
X
X
X
X
Evaluation of PN/I.V.
Xd
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Colonscopy/      
  Sigmoidoscopy
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
Xe
X
X
X
X
X
X
X
Height
X
X
12-lead ECG
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrulline
X
X
X
X
X
Teduglutide concentration 
and antibodies to 
teduglutide and E. coli
protein
X
X
X
PK sampling
Xi
(X)
(X)
(X)
(X)
(X)
Urine pregnancy test
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety evaluationf
[X]g
[X]
[X]
[X]
[X]
[X]
48-hour oral fluid intakeh
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputh
(Diary)
X
X
X
X
X
X
X
X
Diary
X
X
X
X
X
X
X
X
X
Teduglutide dosingj
X
X
X
X
X
X
X
X
X
Compliancek
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 50 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
( X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous (volume); V = visit
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone.
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance.
c A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit.
d The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
e This is the second of 2 body weight measurements that will be used to determine drug volume.
f Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
g At the Visit 4/Week 2 interim safety visit, laboratory evaluations and 48-hour I/O are not required.  These will be assessed only if the PN/I.V. adjustment was 
tolerated.
h All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.
i Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7.
j Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will self-inject the study drug at home.
k Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 51 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First Visita 
(last visit 
for Stage 2)
Mo 
1/13
Mo 
2/14
Mo
3/15
Mo 
4/16 
Mo 
5/17
Mo 
6/18
Mo 
7/19
Mo 
8/20
Mo 
9/21
Mo 
10/22
Mo 
11/23
Mo 
12
Final       
(Mo 24) 
(or early 
termination)
Visit Number:
V1
V2/
14
V3/ 
15
V4/ 
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/ 
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days)
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Eligibility, Informed consent
X
Medical history, 
demographics
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
Height
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
12-lead ECG
X
Xg
X
X
X
Colonoscopy/sigmoidoscopy 
of remnant colon
X
Citrulline
X
X
X
X
X
X
X 
X
Teduglutide concentration 
and antibodies to teduglutide
and E. coli protein
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety visitd
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Diary e
X
X
X
X
X
X
X
X
48-hour oral fluid intakef 
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputf
(Diary)
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 52 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Evaluation of PN/I.V. (actual 
volume L/week)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
[X ] = Possible interim safety evaluation time point (Refer to footnote “d”.); ECG = electrocardiogram; Mo = month; PN/I.V. = parenteral nutrition/intravenous (support); V = visit
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the Month 2 visit.  Interim 
(standard of care) visits may be utilized to assess patients’ well-being (ie, occurrence of adverse events) and to check for any changes in medications.
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed appropriate.
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone.
c Full physical examination to be performed at first and final visit; a brief examination will be performed at all other study visits.
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  Hematocrit, serum blood urea 
nitrogen and serum creatinine, and urine sodium will be measured.
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The measurements should include 
1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily.
g An ECG will be taken at Visit 3, but not at Visit 15.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 53 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s CRF by the investigational site 
staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case of 
computerized source data, the investigator has to give the sponsor access to the subject files at 
each monitoring visit. To ensure that data have been entered correctly on the CRF, they will be 
100% source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding any questions or discrepant data. The investigator or designee will be 
responsible for the timely recording of subject data into the CRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The PI or designee will review all CRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will sign the CRF via an electronic signature. The PI
will be responsible for reviewing the data in a timely manner.  Non-CRF data will be sent to the 
sponsor or designee via a data transfer from the appropriate vendor for assimilation into the 
database. Paper copies non-CRF data will be signed and dated by the investigator and filed.
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with CRF guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that should 
be resolved at the study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 54 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.
An audit will be performed by the Data Management group. When all issues from the audit are 
resolved, and all data management processes are completed for finalizing the database, the 
database will be ready for statistical analysis by NPS or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC. In the event that the appropriate individual at the site provides an 
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 55 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.
8
STATISTICAL METHODOLOGY 
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 56 of 72
Final v2.0, Administrative Amendment 1
20 August 2014

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the LS mean percent change in weekly 
PN/I.V. volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the 
placebo group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, 
PN/I.V. results will be compared with those from Study CL0600-020.  The comparison 
should take into account the anticipated variability of the data due to the small number of 
subjects in Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95%
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with those 
from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should take 
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 57 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
8.2.2
Efficacy and Pharmacodynamics – Stage 3
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.
8.3
Safety – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, laboratory safety data, antibodies to teduglutide, and changes in urine 
output, body weight, and BMI.  See Section 6.2 for a full list of safety variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg., number and percentage of subjects) for each treatment group. Adverse 
events will be summarized by severity, relationship to treatment, AEs leading to discontinuation, 
and AEs leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point for each treatment group. 
The number and percentage of subjects classified as having antibodies to teduglutide will be used to 
summarize the presence of antibodies for each treatment group.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study. 
The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow up. The primary population analyzed for 
efficacy will be the ITT population. An additional per-protocol population analysis will also be 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 58 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
performed as secondary/sensitivity analysis. Detailed per-protocol evaluable definitions will be 
documented in the Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 59 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
NPS SMT has assessed it as an unanticipated problem.  Approval for protocol amendments will 
be transmitted in writing to the investigator.
The investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed one year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject. A subject information/ICF model will be provided by the 
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 60 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods. The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial. IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 61 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 62 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
10
REFERENCES
None


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 63 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
APPENDIX 1:
PN/I.V. OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 64 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
by targeted urine output of 1.0-2.0 L/day.  If a subject has not achieved an optimal tolerated 
volume of PN/I.V. after 8 weeks, consult the NPS Medical Director.
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 65 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to 
reduce volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Monitor.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 66 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table A2-1: PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% (Week 2) or to 
previous level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A2-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of stabilized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Table A2-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 
PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be collected to 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 67 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
evaluate hydration and nutrition (see Table A2-2).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. (Reduction 
of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
Table A2- 3: Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is 
dehydrated (See Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not 
dehydrated, but is inadequately nourished 
(See Table A2-2)
If possible, maintain PN/I.V. volume 
and increase nutrition. If not, increase 
PN/I.V. to previous volumea
Baseline output or greater and subject is 
adequately hydrated and nourished (See 
Table A2-2)
Maintain PN/I.V.
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate increase in PN/I.V.
is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V..
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 68 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  During the 
remainder of the study, subjects may undergo 1 additional attempt to reduce volume by 
at least 10%.
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 69 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of OPTIMIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Director.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 70 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
Table A3- 1: PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% or to previous 
level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A1-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of optimized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily.  All blood and urine samples should be taken at a consistent time period throughout 
the study, convenient for the subject and site staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed after 5 to 7 days of the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. Depending on the 
wellbeing of the subject it is at the discretion of the investigator to abstain from the 
laboratory safety samples.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 71 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.
Table A3-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
* AND consistent with subject’s previous levels prior to study entry.
BUN = blood urea nitrogen; ULN = upper limit of normal
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 72 of 72
Final v2.0, Administrative Amendment 1
20 August 2014
APPENDIX 4:
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study 
in compliance with this protocol, any future amendments, and with any other study conduct procedures 
provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practice 
(GCP) and all other applicable regulatory requirements to obtain written and dated approval from the 
Institutional or Central Review Board (IRB) or Independent Ethics Committee (IRB) for the study 
protocol and any amendments thereof, written informed consent or updates thereof, subject recruitment 
procedures (eg, advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from the 
sponsor and review and documented approval from the IRB, except to eliminate an immediate hazard to 
the study subjects, or when change(s) involves only logistical or administrative aspects of the clinical 
study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by 
the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in 
this protocol, and any other information provided by the sponsor or In-country Clinical Caretaker 
including, but not limited to, the current Investigator’s Brochure or equivalent document and approved 
product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the foreseen 
duration of the clinical study in order to conduct the study properly, ethically, and safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


TEDUGLUTIDE (ALX-0600)
A 3-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 3.0
Phase 3
Sponsor:  NPS Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
USA
Medical Monitor (Medical Expert of the Sponsor):
 MD
 Clinical Development
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-23 Shimomiyabicho, Shinjuku-ku,
Tokyo 162-0822, Japan
TEL:
 FAX:
Protocol v1.0:
05 August 2014
Protocol v2.0, Amendment 1:
20 August 2014 (administrative amendment)
Protocol v3.0, Amendment 1 (corrected)
15 September 2014
The information contained in this document is the property of NPS Pharmaceuticals, Inc. It is 
understood that the information will not be disclosed to others aside from the investigator(s) and duly 
designated staff, applicable IRB(s) and regulatory authorities without prior written approval from NPS 
Pharmaceuticals Inc., except to the extent necessary to obtain informed consent from those persons to 
whom the study drug may be administered.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 2 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
SUMMARY
Protocol TED-C14-004
Title of Study: A 3-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 3-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous volume (PN/I.V.) support optimization period; and a 
stabilization period in which stable administration of PN/I.V. support, defined as a targeted 
urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and nourished,
is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a subject fails to 
remain stable for at least 4 consecutive weeks, the subject may start the optimization period 
again, beginning with Visit 1.1. Those subjects who fail to stabilize after 2 attempts will not 
proceed further and will not be dosed. Stage 2 will be a dosing period of 24 weeks, during 
which subjects will self-administer the study drug at home.
Stage 3 is the long-term extension portion of the study, which will begin immediately 
following Stage 2.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 
24 months or until regulatory approval and commercial availability of teduglutide in Japan. 
(After the approval of marketing authorization, the study will continue as a post-marketing 
clinical study until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled during the recruitment 
period, which ends approximately 6 months after the initiation of the study.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 3 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:
o
Actual PN/I.V. usage matches prescribed PN/I.V.
o
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.
o
Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function: 
o
Total bilirubin < 2 times upper limit of normal (ULN)
o
Aspartate aminotransferase (AST) < 5 times ULN
o
Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function:
o
Serum creatinine < 2 times ULN
o
Creatinine clearance ≥50 mL/minute

Adequate pancreatic function:
o
Serum amylase < 2 times ULN
o
Serum lipase < 2 times ULN


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 4 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC)
injection is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile 
water for injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study.
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen or either thigh or arm. The first SC injection should be administered under the 
supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period; and a stabilization period that demonstrates stable administration 
of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks (total maximum
16 weeks for optimization/stabilization periods).  Subjects who fail optimization may repeat 
this period (taking up to an additional 16 weeks).  Therefore the total possible duration of 
Stage 1 is up to 33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue in the extension 
treatment period for up to an additional 24 months (Stage 3) or until teduglutide is 
commercially available, whichever comes first. (After the approval of marketing 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 5 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
authorization, the study will continue as a post-marketing clinical study in order to 
continuously provide teduglutide to the subjects until the product is commercially available).
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stage 3:  Absolute and percent change from baseline in 
weekly PN/I.V. volume and changes in days per week of PN/I.V. support and plasma 
citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose pharmacokinetics will be evaluated on the 
first day of teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected 
pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
Safety – All Stages:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, 
laboratory safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 6 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
changes in urine output (48-hour I/O), body weight and body mass index (BMI) will be 
evaluated.  An abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will 
be done at the end of the optimization period if these procedures were not done in the 
6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated at the end of the 
main treatment period (Stage 2) and at the end of the extension treatment period (Stage 3).  
For all subjects with a history of Crohn’s disease, an upper gastrointestinal (GI) contrast series 
with small bowel follow through will be performed during the stabilization period, prior to the 
baseline visit.
Statistical methods:  No formal testing will be conducted for efficacy variables.  For 
continuous variables, descriptive statistics will be used to summarize median, maximum, 
minimum, mean (± standard deviation [SD]), geometric mean (± standard error [SE]) and its 
95% confidence interval.  For categorical variables, n (%) will be summarized.  Individual 
data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the 
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 8 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Reviewed:
Japan


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 9 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................1
SUMMARY ....................................................................................................................................2
SIGNATURE PAGE......................................................................................................................7
TABLE OF CONTENTS ..............................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................14
1
INTRODUCTION..................................................................................................................16
1.1
Background.....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design.............................................................................................19
2
OBJECTIVES ........................................................................................................................19
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2 ....................................................19
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3 ....................................................20
2.3
Pharmacokinetic Endpoints – Stage 2 Only....................................................................20
2.4
Safety Objectives – All Stages........................................................................................20
3
STUDY DESIGN....................................................................................................................21
3.1
Main Treatment Period (Stages 1 and 2) ........................................................................21
3.2
Extension Treatment Period (Stage 3)............................................................................21
4
SUBJECT SELECTION AND PARTICIPATION............................................................24
4.1
Number of Subjects.........................................................................................................24
4.2
Inclusion Criteria ............................................................................................................24
4.2.1
Inclusion in Stage 3..........................................................................................25
4.3
Exclusion Criteria ...........................................................................................................25
4.4
Subject Withdrawal Criteria ...........................................................................................28
4.4.1
Events Necessitating Withdrawal from Study.................................................28
4.4.2
Re-screening of Subjects..................................................................................29
5
TREATMENTS AND TREATMENT PLAN .....................................................................29
5.1
Treatments Administered................................................................................................30
5.1.1
Identification of Investigational Product .........................................................30


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 10 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
5.1.2
Packaging and Labeling...................................................................................30
5.1.3
Storage, Accountability, and Stability.............................................................31
5.2
Dose Regimen.................................................................................................................31
5.2.1
Selection of Doses in Study.............................................................................31
5.2.2
Selection and Timing of Dose for Each Subject..............................................32
5.2.3
Subjects Who Achieve PN/I.V. Independence ................................................32
5.2.4
Compliance with Dosing Regimens.................................................................33
5.3
Prior and Concomitant Medications ...............................................................................33
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................33
6.1
Efficacy Evaluations.......................................................................................................33
6.2
Safety Evaluations ..........................................................................................................34
6.2.1
Adverse Events ................................................................................................34
6.2.2
Serious Adverse Events ...................................................................................37
6.2.3
Pregnancy Reporting........................................................................................40
6.2.4
Laboratory Evaluations....................................................................................40
6.2.5
Plasma Citrulline..............................................................................................42
6.2.6
Women of Child Bearing Potential..................................................................42
6.2.7
48-Hour Oral Fluid Intake and Urine Output ..................................................42
6.2.8
Clinical Assessment of Crohn’s Disease Activity ...........................................43
6.2.9
Subject Diaries.................................................................................................43
6.2.10
Changes in PN/I.V. Volume ............................................................................43
6.2.11
Medical History and Demographics ................................................................43
6.2.12
Concomitant Medication Assessment..............................................................44
6.2.13
Physical Examinations.....................................................................................44
6.2.14
Vital Signs and Body Weight ..........................................................................44
6.2.15
Electrocardiograms ..........................................................................................44
6.2.16
Gastrointestinal-specific Testing .....................................................................45
6.3
Pharmacokinetic Evaluations..........................................................................................45
6.4
Schedule of Evaluations and Procedures........................................................................46
7
DATA MANAGEMENT.......................................................................................................53
7.1
Data Collection ...............................................................................................................53
7.2
Record Retention ............................................................................................................54


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 11 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
7.3
Quality Control ...............................................................................................................54
8
STATISTICAL METHODOLOGY.....................................................................................55
8.1
Demographic and Baseline Variables.............................................................................55
8.2
Efficacy and Pharmacodynamic Variables .....................................................................55
8.2.1
Efficacy and Pharmacodynamics – Stage 2.....................................................55
8.2.2
Efficacy and Pharmacodynamics – Stage 3.....................................................57
8.3
Safety – All Stages..........................................................................................................57
8.3.1
Statistical Methods for Safety Variables..........................................................57
8.4
Pharmacokinetic Variables – Stage 2 Only ....................................................................57
8.5
Analysis Populations, Data Sets, and Time Points .........................................................57
8.5.1
Analysis Populations........................................................................................57
8.6
Statistical/Analytical Issues ............................................................................................58
8.6.1
Adjustments for Covariates..............................................................................58
8.6.2
Handling of Dropouts or Missing Data............................................................58
8.6.3
Interim Analyses ..............................................................................................58
8.6.4
Multiple Comparisons/Multiplicity .................................................................58
8.6.5
Use of an Efficacy Subset of Subjects.............................................................58
8.6.6
Examination of Subgroups...............................................................................58
8.7
Determination of Sample Size ........................................................................................58
8.8
Changes to Planned Statistical Analyses ........................................................................59
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................59
9.1
Declaration of Helsinki and Ethical Review...................................................................59
9.2
Subject Information and Consent....................................................................................59
9.3
Subject Data Protection...................................................................................................60
9.4
Payment and Compensation............................................................................................60
9.5
Changes to the Protocol ..................................................................................................60
9.6
Confidentiality/Publication of the Study ........................................................................61
9.7
Study Termination ..........................................................................................................61
10 REFERENCES.......................................................................................................................62
APPENDIX 1:
PN/I.V. OPTIMIZATION.............................................................................63


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 12 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2).............................................................................................................65
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3) .................................................................................69
APPENDIX 4:  PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE......72


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 13 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
LIST OF TABLES AND FIGURES
Table 4-1
Excluded Diseases and Illnesses..........................................................................27
Table 6-1
Schedule of Evaluations and Procedures – Stage 1...........................................47
Table 6-2
Schedule of Evaluations and Procedures – Stage 2...........................................49
Table 6-3: 
Schedule of Evaluations and Procedures – Stage 3 (Extension)......................51
Figure 3-1
Study Diagram .....................................................................................................23


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 14 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NPS
NPS Pharmaceuticals, Inc.
PI
Principal Investigator
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 15 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
PN/I.V.
Parenteral Nutrition/Intravenous (volume)
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SMT
Safety Management Team
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 16 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
1
INTRODUCTION
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 17 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats. In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 18 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.
Clinical Studies
Results of the pivotal study filed for the US New Drug Application, CL0600-020, showed that 
teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing 
parenteral nutrition/intravenous (PN/I.V.) volume in adult subjects with SBS.  In this study the 
responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects achieving a 
mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and in the United States (US).  The clinical 
profile and issues related to SBS and PN/I.V. in Japan are similar to those in the EU and in the 
US.    Therefore, there is an unmet medical need for Japanese patients with PN-dependent SBS.  
This study is designed to provide evidence of safety and efficacy of teduglutide in a Japanese 
SBS patient population. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 19 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
2
OBJECTIVES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period followed by a 
long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 20 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3
For Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes 
in days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0). 
Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 
3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
2.4
Safety Objectives – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done at the end of the optimization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(Stage 3).  For all subjects with a history of Crohn’s disease, an upper GI contrast series with 
small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 21 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
3
STUDY DESIGN
This will be an open-label, multicenter, 3-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stage 3).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. reduction and optimization 
period (if required); and a stabilization period that demonstrates stable PN/I.V. support for a 
minimum of 4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stage 3)
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2 and will include subjects who complete the main treatment period and who are willing to 
continue teduglutide treatment.  Subjects will continue to receive teduglutide 0.05 mg/kg/day SC 
for up to an additional 24 months or until teduglutide is commercially available, whichever 
comes earlier. (After the approval of marketing authorization, the study will continue as a 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 22 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
post-marketing clinical study to continuously provide teduglutide to the subjects until the product 
is commercially available.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 23 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V. 
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months or until 
Regulatory Approval
Stage 3


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 24 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Schedules of evaluations for Stage 1, 2 and 3 can be found in Table 6-1, Table 6-2 and Table 6-3, 
respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization and treatment periods can 
be found in Appendix 1 and Appendix 2, respectively, and should be followed carefully 
throughout the study.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled during the recruitment period, 
which ends approximately 6 months after the initiation of the study.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1. Signed and dated Informed Consent Form (ICF) before any study-related procedures 
are performed
2. Men and women, 16 years of age or older at the time of signing the ICF 
3. Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/I.V. dependency prior to signature of ICF
4. For subjects with a history of Crohn’s disease, the subject should be in clinical 
remission for at least 12 weeks prior to dosing as demonstrated by clinical 
assessment, which may include procedure-based evidence of remission.
5. PN/I.V. requirement of at least 3 times per week during the week before screening 
and during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6. Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the 
start of teduglutide treatment, based upon the opinion of the investigator and approval 
by the sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b. Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time subject is 
optimized and enters stabilization
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 25 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 of this study:
1. Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1. Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or 
concurrent participation in any clinical study using an experimental drug that would 
affect the safety of teduglutide
2. Previous use of native GLP-2 or human growth hormone within 6 months prior to 
screening
3. Previous use of intravenous glutamine, octreotide, GLP-1 analog , or dipeptidyl 
peptidase-IV inhibitors within 30 days prior to screening
4. Previous use of teduglutide
5. Serial transverse enteroplasty or any other bowel lengthening procedure performed 
within the past 3 months
6. Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed 
during the 6 months prior to screening
7. Subjects with inflammatory bowel disease who require chronic systemic 
immunosuppressant therapy that was introduced or changed during the last 3 months
8. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9. Radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening
11. Major GI surgical intervention within 3 months prior to screening (insertion of 
feeding tube or endoscopic procedure is allowed)
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell 
carcinoma within 5 years
14. Active clinically significant pancreatic or biliary disease


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 26 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, 
bowel obstruction, severe water-electrolyte disturbances) within12 months prior to 
screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b. Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function:
a.
Serum creatinine ≥2 times ULN
b. Creatinine clearance < 50 mL/minute
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results 
including:
a.
Serum amylase level ≥2 times ULN
b. Serum lipase level ≥2 times ULN
20. Pregnant or lactating women
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years 
or older and/or at least 2 years had elapsed since her last menses) or who are not 
using medically acceptable methods of birth control during and for 30 days after the 
treatment period
22. Not capable of understanding or not willing to adhere to the study visit schedule and 
other protocol requirements
23. Evidence of untreated intestinal obstruction or active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevented completion of the study, or interfered with analysis of the study 
results
25. Presence of any of the excluded disease states described in Table 4-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 27 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue 
due to radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the 
last 3 months
Crohn’s disease or other diseases that require biological therapy (eg, 
anti-tumor necrosis factor or natalizumab) that was introduced or 
changed in the last 6 months
Untreated known pre-malignant or malignant change in upper or 
lower GI biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile 
polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada syndrome, 
Eversmeyerous polypius)
Intestinal or other major surgery scheduled within the time frame of 
the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency 
syndrome, severe combined immunodeficiency), hypersensitivity or 
allergies to teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or 
central nervous system)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 28 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 
procedures described in Section 6.2.1.2.  As far as possible, all examinations scheduled for the 
end-of-study evaluations must be performed on all subjects who participate, but do not complete 
the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere with 
analysis of the study results (ie, compromise PN/I.V.):
      o Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that would put
the subject at any undue risk or prevent completion of the study
o Major surgical interventions (eg, abdominal, vascular)
o Crohn’s disease flare up
o Use of any excluded medication
o Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/ Sponsor decision (ie. subject non-compliance with study procedures)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 29 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of NPS. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.
5
TREATMENTS AND TREATMENT PLAN
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the dosing period is in
Appendix 2.
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2.  In Stage 3, subjects can continue teduglutide treatment if deemed appropriate by the 
investigator.  During the extension, the PN/I.V. dosage will be adjusted as described in 
Appendix 3.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 24 months or 
until regulatory approval and commercial availability of teduglutide in Japan.  (After the 
approval of marketing authorization, the study will continue as a post-marketing clinical study 
until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during Stage 2 or 3) will continue to receive teduglutide treatment.  If 
a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 30 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
5.1
Treatments Administered 
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen.
5.1.1
Identification of Investigational Product 
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.
Active ingredient:
teduglutide
Added ingredients:
L-histidine, mannitol, monobasic and dibasic sodium 
phosphate
Route of administration:
SC injection
Dose:
0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and ICCC name and address. All medication supplied to be used in this study will be 
manufactured, tested, labeled, and released according to current legal requirements and Good 
Manufacturing Practice.  Ancillary supply kits containing the following will also be provided 
with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution

Syringes with needles for injection (dosing)

Alcohol swabs


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 31 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 32 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets and the study reference manual. Each day, the 
injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.
Dosing must be performed at least 14 hours prior to antibody testing, which will be performed at 
baseline and at Weeks 12 and 24 during Period 2 and at Months 6, 12, and 24 during Period 3. 
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues. 
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive
teduglutide treatment.  A subject will be considered to have achieved independence from PN/I.V. 
(completely weaned off PN) if the investigator prescribes no PN and there is no use of PN 
recorded in the subject diary at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 33 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded in the appropriate sections of the CRF.
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, warfarin, psychotropics, and digoxin), so consideration should be given 
to modifying concomitant medication regimens.  Down-titration of concomitant medication 
dosages should be considered when drugs, including those with a narrow therapeutic range, are 
given, especially if given at dosages that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stage 3) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 and 3 of this study are given in 
Appendix 2 and Appendix 3, respectively.
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 34 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes in 
days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms 

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP.  Samples for antibody analysis will be drawn at the start 
of treatment and at the EOT visit (prior to the administration of teduglutide and at least 
14 hours after the previous dose).  A 6-month follow-up is planned for any subjects testing 
positive for teduglutide-specific antibodies following the last dose of study drug.

Changes in urine output (48-hour oral fluid intake/urine output)

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 35 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 36 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form.  This information will be shared 
with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF through the last dose of study drug.  Adverse events that are not resolved at 
the end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility 

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 37 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s 
medical history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form.  An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug will be captured and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 38 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
enter the SAE information into the SAE reporting system and fax supplemental data (eg, medical 
records or laboratory values, if applicable) to the sponsor. This ensures timely reporting of 
applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
The sponsor or designee will provide a FAX cover sheet for the investigators in the study 
reference manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 39 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect study 
product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related) 

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the study reference manual.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not reported in the clinical safety section of the Investigator Brochure (IB) or if the event is of 
greater frequency, specificity, or severity than is mentioned in the IB.  The investigator will 
receive a copy of the current valid version of the IB prior to the start of the study; however, the 
investigator will not be required to assess expectedness, nor should expectedness impact the 
investigator reporting SAEs within the timeframe herein defined.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 40 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Upon receiving such notices, the investigator must review and retain the notice.  If it is 
determined that there is an unanticipated signal, the NPS SMT will analyze the data and prepare 
a summary supporting the determination and interpretation of the findings.  The sponsor or 
designee will send this summary to the investigators with instructions to provide it to their
Institutional Review Board (IRB).
The investigator should also comply with the IRB procedures for reporting any other safety 
information (ie, autopsy reports).  
NPS Pharmaceuticals, Inc. or its designee will be responsible for submitting SUSAR reports to 
the appropriate health authorities.  These reports will be submitted within the expedited
timeframe.
6.2.3
Pregnancy Reporting
In the event a subject becomes pregnant during the study, study drug will be discontinued and an 
SAE form will be completed to capture potential drug exposure during pregnancy. This will be 
reported within 24 hours of becoming aware of the pregnancy. The subject will be followed up 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
[miscarriage], voluntary abortion, or therapeutic abortion). If a pregnant subject also experiences 
an SAE, an additional SAE form will be completed and submitted within 24 hours as discussed 
above. 
In the event a female partner of a male subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator (PI) and a supplemental SAE form will be completed to 
capture the event.
6.2.4
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
The site’s clinical laboratory will centrifuge and send the samples to the central lab, SRL 
Medisearch Inc. SRL Medisearch will analyze those specimens while sending the citrulline、
antibody, and PK samples to NPS headquarters in the U.S.
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs, if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 41 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2 and Table 6-3.
Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 
Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; total, direct, and indirect bilirubin; blood 
urea nitrogen; calcium; chloride; total-cholesterol; C-reactive protein; creatinine; creatinine 
clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; potassium; 
sodium; triglycerides; and uric acid
Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  
Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)
Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 or early termination during Stage 2 of the study, and at Months 6 and 12, 
and at the final visit or early termination in Stage 3.
If teduglutide-specific antibodies are detected, subjects may remain in study and will continue to 
be tested at each visit, as long as there are no concurrent AEs associated with immunogenicity.  
Subjects who test positive for teduglutide-specific antibodies at the end of Stage 2 will be 
allowed to enter Stage 3, as long as there are no concurrent AEs associated with 
immunogenicity.  The presence of teduglutide-specific antibodies will continue to be monitored 
at every visit until the end of this study.  If, at the final visit, the subject is still positive for 
teduglutide-specific antibodies, the subject will require follow-up blood draws as specified 
above. If any subject (previously negative for teduglutide antibodies) has specific 
anti-teduglutide antibodies at the final visit of this study, they will have follow-up blood draws 
for antibodies at Months 2, 3 and 6 post-study.  These may be done at a local laboratory
convenient to the subject, however all blood samples will be mailed to the central laboratory for 
analysis.  If a subject’s results are negative at 2 successive visits within this time, follow-up may 
be terminated.  If at the end of 6 months the subject is still determined to have 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 42 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
teduglutide-specific antibodies, the PI and the sponsor will determine if additional follow-up 
may be required.  During this follow-up, subjects will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilence database.  Collection of AE 
and/or SAE information may be done via telephone contact. 
Teduglutide Concentrations
Teduglutide concentrations will be determined in the blood samples collected for antibody 
testing, ie, at baseline and at Weeks 12, 24 or early termination during Stage 2 of the study, and 
at Months 6, 12, and at the final visit or early termination in Stage 3.
6.2.5
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2 and Table 6-3).  If peripheral venous access 
is not possible, blood samples for citrulline may be drawn from a central line.  The samples will 
be processed according to instructions in the laboratory manual.
6.2.6
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.7
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 
Stages 1 and 2 and at the visits specified in Table 6-3 during Stage 3. The center staff will 
contact the subject at least 48 hours before the scheduled visits to remind the subject to start 
measuring complete I/O, and to record these measurements into the diary.  At these times of 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 43 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at any required interim safety visit.
6.2.8
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 2 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.9
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
optimization and stabilization periods and the treatment periods in Stages 2 and 3 of the study.
6.2.10
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the PN/I.V. volume is adjusted as a result of a TEAE that 
is not related to study drug, then the diary data will not be included in the data analysis. If the 
subject has a TEAE that prevents him or her from adhering to study requirements, including PN 
adjustments, the subject may be withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 and 3 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.
6.2.11
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 44 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
6.2.12
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each visit and the details of any medications and changes therein (change in medication or 
dosage of medication) will be recorded on the CRF.
6.2.13
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and at the final visits of Stage 2 and Stage 3.  A brief examination of the GI and cardiovascular 
systems will be made at all other study visits.  Other body systems will be examined as clinically 
indicated.
6.2.14
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, and Table 6-3). Vital signs will include systolic and diastolic blood pressure 
(mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been sitting for 
5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded at the 
initial visits of Stages 1, 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.15
Electrocardiograms
A 12-lead ECG will be performed at Week 2 during Stage 1, at baseline, Week 4, and at the final 
visit during Stage 2, and at the first visit (last visit for Stage 2) and at Months 2 and 6 and the 
final visit during Stage 3.  The ECG will be done at the study center after the subject has been 
resting for at least 5 minutes.  Results will include general findings only (normal/abnormal).  
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 45 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
6.2.16
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1 , Table 6-2, and Table 6-3) for details and scheduling.
6.2.16.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2 and at the end of teduglutide 
exposure in Stage 3.  A colonoscopy is required at the beginning of the study, at the end of the 
main treatment period and at the end of the study to determine if any clinically significant 
changes have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a 
subject had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.
6.2.16.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0)
in Stage 2 of the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 
minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2

CL/F

V/F


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 46 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures – Stage 3, 
Table 6-3.
Subjects who drop out of the study prior to the final visit should have all end-of-study procedures 
done. 




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 48 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 6-1
Schedule of Evaluations and Procedures – Stage 1
Procedures
Prior to
screening
Screening
(7-day 
maximum)
PN/I.V. Optimization Period l
(8-week maximum)
PN/I.V. 
Stabilization 
Period
4-8 weeks 
(± 7 days)
Week 2
(± 3 days)
Week 4 
(± 3 days
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
[X ] = possible interim safety evaluation time point (Refer to footnote “i”.); BMI = body mass index; ECG = electrocardiogram; PN/I.V. = parenteral 
nutrition/intravenous (volume); V = visit
l One re-challenge of the optimization/stabilization is permitted
a ICF must be signed before the start of the 48-hour urine output measurements and any other study-related procedures.
b A full physical examination is to be performed at screening.
c PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
d Abdominal ultrasound should be completed during the stabilization period, prior to the baseline visit if not performed within 6 months prior to screening.
e Upper GI contrast series with small bowel follow-through is required for patients with Crohn’s disease.  This should be completed during the stabilization 
period, prior to the baseline visit.
f Colonoscopy/sigmoidoscopy of remnant colon with polyp removal before teduglutide exposure will be performed in patients with any colon remnant including 
rectal stump evaluation. Colonoscopy should be completed during the stabilization period, prior to the baseline visit, if required. If a subject had a normal 
colonoscopy/sigmoidoscopy within 6 months prior to screening, a baseline colonoscopy/sigmoidoscopy will not be required.
g At screening, information on all medications taken in the previous 30 days will be collected.
h This is the first of 2 body weight measurements that will be used to determine drug volume.
i Interim safety evaluations will be done 5 to 7 days after any scheduled visit where a PN/I.V. change was made.  These measures include 48-hour oral fluid
intake, 48-hour urine volume, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
j An interim safety evaluation should be conducted toward the end of the stabilization period to determine that the subject is compliant with Inclusion Criterion 6 
(stable PN/I.V.) and Exclusion Criteria 17 (hepatic function) and 18 (renal function).
k All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 49 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
Eligibility criteria
X
Crohn’s disease assessment
X
Physical examinationc
X
X
X
X
X
X
X
X
Evaluation of PN/I.V.
Xd
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Colonscopy/      
  Sigmoidoscopy
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
Xe
X
X
X
X
X
X
X
Height
X
X
12-lead ECG
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrulline
X
X
X
X
X
Teduglutide concentration 
and antibodies to 
teduglutide and E. coli
protein
X
X
X
PK sampling
Xi
(X)
(X)
(X)
(X)
(X)
Urine pregnancy test
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety evaluationf
[X]g
[X]
[X]
[X]
[X]
[X]
48-hour oral fluid intakeh
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputh
(Diary)
X
X
X
X
X
X
X
X
Diary
X
X
X
X
X
X
X
X
X
Teduglutide dosingj
X
X
X
X
X
X
X
X
X
Compliancek
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 50 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
( X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous (volume); V = visit
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone.
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance.
c A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit.
d The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
e This is the second of 2 body weight measurements that will be used to determine drug volume.
f Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
g At the Visit 4/Week 2 interim safety visit, laboratory evaluations and 48-hour I/O are not required.  These will be assessed only if the PN/I.V. adjustment was 
tolerated.
h All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.
i Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7.
j Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will self-inject the study drug at home.
k Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 51 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First Visita 
(last visit 
for Stage 2)
Mo 
1/13
Mo 
2/14
Mo
3/15
Mo 
4/16 
Mo 
5/17
Mo 
6/18
Mo 
7/19
Mo 
8/20
Mo 
9/21
Mo 
10/22
Mo 
11/23
Mo 
12
Final       
(Mo 24) 
(or early 
termination)
Visit Number:
V1
V2/
14
V3/ 
15
V4/ 
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/ 
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days)
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Eligibility, Informed consent
X
Medical history, 
demographics
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
Height
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
12-lead ECG
X
Xg
X
X
X
Colonoscopy/sigmoidoscopy 
of remnant colon
X
Citrulline
X
X
X
X
X
X
X 
X
Teduglutide concentration 
and antibodies to teduglutide
and E. coli protein
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety visitd
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Diary e
X
X
X
X
X
X
X
X
48-hour oral fluid intakef 
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputf
(Diary)
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 52 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table 6-3:
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Evaluation of PN/I.V. (actual 
volume L/week)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
[X ] = Possible interim safety evaluation time point (Refer to footnote “d”.); ECG = electrocardiogram; Mo = month; PN/I.V. = parenteral nutrition/intravenous (support); V = visit
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the Month 2 visit.  Interim 
(standard of care) visits may be utilized to assess patients’ well-being (ie, occurrence of adverse events) and to check for any changes in medications.
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed appropriate.
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone.
c Full physical examination to be performed at first and final visit; a brief examination will be performed at all other study visits.
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  Hematocrit, serum blood urea 
nitrogen and serum creatinine, and urine sodium will be measured.
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The measurements should include 
1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily.
g An ECG will be taken at Visit 3, but not at Visit 15.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 53 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s CRF by the investigational site 
staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case of 
computerized source data, the investigator has to give the sponsor access to the subject files at 
each monitoring visit. To ensure that data have been entered correctly on the CRF, they will be 
100% source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding any questions or discrepant data. The investigator or designee will be 
responsible for the timely recording of subject data into the CRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The PI or designee will review all CRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will sign the CRF via an electronic signature. The PI
will be responsible for reviewing the data in a timely manner.  Non-CRF data will be sent to the 
sponsor or designee via a data transfer from the appropriate vendor for assimilation into the 
database. Paper copies non-CRF data will be signed and dated by the investigator and filed.
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with CRF guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that should 
be resolved at the study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 54 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.
An audit will be performed by the Data Management group. When all issues from the audit are 
resolved, and all data management processes are completed for finalizing the database, the 
database will be ready for statistical analysis by NPS or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC. In the event that the appropriate individual at the site provides an 
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 55 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.
8
STATISTICAL METHODOLOGY 
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 56 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the LS mean percent change in weekly 
PN/I.V. volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the 
placebo group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, 
PN/I.V. results will be compared with those from Study CL0600-020.  The comparison 
should take into account the anticipated variability of the data due to the small number of 
subjects in Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95%
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with those 
from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should take 
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 57 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
8.2.2
Efficacy and Pharmacodynamics – Stage 3
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.
8.3
Safety – All Stages
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, laboratory safety data, antibodies to teduglutide, and changes in urine 
output, body weight, and BMI.  See Section 6.2 for a full list of safety variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg., number and percentage of subjects) for each treatment group. Adverse 
events will be summarized by severity, relationship to treatment, AEs leading to discontinuation, 
and AEs leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point for each treatment group. 
The number and percentage of subjects classified as having antibodies to teduglutide will be used to 
summarize the presence of antibodies for each treatment group.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study. 
The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow up. The primary population analyzed for 
efficacy will be the ITT population. An additional per-protocol population analysis will also be 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 58 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
performed as secondary/sensitivity analysis. Detailed per-protocol evaluable definitions will be 
documented in the Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 59 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
NPS SMT has assessed it as an unanticipated problem.  Approval for protocol amendments will 
be transmitted in writing to the investigator.
The investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed one year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject. A subject information/ICF model will be provided by the 
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 60 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods. The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial. IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 61 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 62 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
10
REFERENCES
None


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 63 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
APPENDIX 1:
PN/I.V. OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 64 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
by targeted urine output of 1.0-2.0 L/day.  If a subject has not achieved an optimal tolerated 
volume of PN/I.V. after 8 weeks, consult the NPS Medical Director.
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 65 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to 
reduce volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Monitor.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 66 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table A2-1: PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% (Week 2) or to 
previous level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A2-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of stabilized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Table A2-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 
PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be collected to 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 67 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
evaluate hydration and nutrition (see Table A2-2).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. (Reduction 
of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
Table A2- 3: Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is 
dehydrated (See Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not 
dehydrated, but is inadequately nourished 
(See Table A2-2)
If possible, maintain PN/I.V. volume 
and increase nutrition. If not, increase 
PN/I.V. to previous volumea
Baseline output or greater and subject is 
adequately hydrated and nourished (See 
Table A2-2)
Maintain PN/I.V.
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate increase in PN/I.V.
is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V..
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 68 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  During the 
remainder of the study, subjects may undergo 1 additional attempt to reduce volume by 
at least 10%.
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 69 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of OPTIMIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Director.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 70 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
Table A3- 1: PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% or to previous 
level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A1-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of optimized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily.  All blood and urine samples should be taken at a consistent time period throughout 
the study, convenient for the subject and site staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed after 5 to 7 days of the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. Depending on the 
wellbeing of the subject it is at the discretion of the investigator to abstain from the 
laboratory safety samples.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 71 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.
Table A3-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
* AND consistent with subject’s previous levels prior to study entry.
BUN = blood urea nitrogen; ULN = upper limit of normal
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 72 of 72
Final v3.0, Amendment 1 (corrected)
15 September 2014
APPENDIX 4:
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study 
in compliance with this protocol, any future amendments, and with any other study conduct procedures 
provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practice 
(GCP) and all other applicable regulatory requirements to obtain written and dated approval from the 
Institutional or Central Review Board (IRB) or Independent Ethics Committee (IRB) for the study 
protocol and any amendments thereof, written informed consent or updates thereof, subject recruitment 
procedures (eg, advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from the 
sponsor and review and documented approval from the IRB, except to eliminate an immediate hazard to 
the study subjects, or when change(s) involves only logistical or administrative aspects of the clinical 
study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by 
the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in 
this protocol, and any other information provided by the sponsor or In-country Clinical Caretaker 
including, but not limited to, the current Investigator’s Brochure or equivalent document and approved 
product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the foreseen 
duration of the clinical study in order to conduct the study properly, ethically, and safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


TEDUGLUTIDE (ALX-0600)
A 3-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 4.0
Phase 3
Sponsor:  
NPS Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
USA
Medical Monitor (Medical Expert of the Sponsor):
 MD
 Clinical Development
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-23 Shimomiyabicho, Shinjuku-ku,
Tokyo 162-0822, Japan
TEL:
FAX:
Protocol v1.0:
05 August 2014
Protocol v2.0, Amendment 1:
20 August 2014 (administrative amendment)
Protocol v3.0, Amendment 1 (corrected)
15 September 2014
Protocol v4.0, Amendment 2
03 March 2015
The information contained in this document is the property of NPS Pharmaceuticals, Inc. It is 
understood that the information will not be disclosed to others aside from the investigator(s) and duly 
designated staff, applicable IRB(s) and regulatory authorities without prior written approval from NPS 
Pharmaceuticals Inc., except to the extent necessary to obtain informed consent from those persons to 
whom the study drug may be administered.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 2 of 72
Protocol v 4.0, Amendment 2
03 March 2015
SUMMARY
Protocol TED-C14-004
Title of Study: A 3-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 3-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous volume (PN/I.V.) support optimization period (if 
required); and a stabilization period in which stable administration of PN/I.V. support, defined 
as a targeted urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and 
nourished, is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a 
subject fails to remain stable for at least 4 consecutive weeks, the subject may start the 
optimization period again, beginning with Visit 1.1. Those subjects who fail to stabilize after 
2 attempts will not proceed further and will not be dosed. Stage 2 will be a dosing period of 
24 weeks, during which subjects will self-administer the study drug at home.
Stage 3 is the long-term extension portion of the study, which will begin immediately 
following Stage 2.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 
24 months or until regulatory approval and commercial availability of teduglutide in Japan. 
(After the approval of marketing authorization, the study will continue as a post-marketing 
clinical study until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled during the recruitment 
period, which ends approximately 6 months after the initiation of the study.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 3 of 72
Protocol v4.0, Amendment 2
03 March 2015
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:
o
Actual PN/I.V. usage matches prescribed PN/I.V.
o
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.
o
Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function at the time of stabilization: 
o
Total bilirubin < 2 times upper limit of normal (ULN)
o
Aspartate aminotransferase (AST) < 5 times ULN
o
Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function at the time of stabilization:
o
Serum creatinine < 2 times ULN
o
Creatinine clearance ≥50 mL/minute (only in subjects with a known history of 
creatinine clearance < 50 mL/min)

Adequate pancreatic function at the time of stabilization:
o
Serum amylase < 2 times ULN
o
Serum lipase < 2 times ULN


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 4 of 72
Protocol v4.0, Amendment 2
03 March 2015

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC)
injection is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile 
water for injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study.
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen or either thigh or arm. The first SC injection should be administered under the 
supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period (if required); and a stabilization period that demonstrates stable 
administration of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks
(total maximum 16 weeks for optimization/stabilization periods).  Subjects who fail 
optimization may repeat this period (taking up to an additional 16 weeks).  Therefore the total 
possible duration of Stage 1 is up to 33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue in the extension 
treatment period for up to an additional 24 months (Stage 3) or until teduglutide is 
commercially available, whichever comes first. (After the approval of marketing 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 5 of 72
Protocol v4.0, Amendment 2
03 March 2015
authorization, the study will continue as a post-marketing clinical study in order to 
continuously provide teduglutide to the subjects until the product is commercially available).
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stage 3:  Absolute and percent change from baseline in 
weekly PN/I.V. volume and changes in days per week of PN/I.V. support and plasma 
citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose pharmacokinetics will be evaluated on the 
first day of teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected
and recorded pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours 
post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 6 of 72
Protocol v4.0, Amendment 2
03 March 2015
Safety:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory 
safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and changes in 
48-hour urine output, body weight and body mass index (BMI) will be evaluated.  An 
abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will be done during 
the stabilization period if these procedures were not done in the 6 months prior to screening.  
Colonoscopy/sigmoidoscopy will be repeated at the end of the main treatment period 
(Stage 2) and at the end of the extension treatment period (Stage 3).  For all subjects with a 
history of Crohn’s disease, an upper gastrointestinal (GI) contrast series with small bowel 
follow-through will be performed during the stabilization period, prior to the baseline visit.
Statistical methods:  No formal testing will be conducted for efficacy or pharmacodynamic 
variables.  For continuous variables, descriptive statistics will be used to summarize median, 
maximum, minimum, mean (± standard deviation [SD]), geometric mean (± standard error
[SE]) and its 95% confidence interval.  For categorical variables, n (%) will be summarized.  
Individual data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the 
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.






Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 8 of 72
Protocol v4.0, Amendment 2
03 March 2015
Reviewed:
 
Japan


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 9 of 72
Protocol v4.0, Amendment 2
03 March 2015
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................1
SUMMARY ....................................................................................................................................2
SIGNATURE PAGE......................................................................................................................7
TABLE OF CONTENTS ..............................................................................................................9
LIST OF TABLES AND FIGURES...........................................................................................13
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................14
1
INTRODUCTION..................................................................................................................16
1.1
Background.....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design.............................................................................................19
2
OBJECTIVES ........................................................................................................................19
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2 ....................................................19
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3 ....................................................20
2.3
Pharmacokinetic Endpoints – Stage 2 Only....................................................................20
2.4
Safety Objectives ............................................................................................................20
3
STUDY DESIGN....................................................................................................................21
3.1
Main Treatment Period (Stages 1 and 2) ........................................................................21
3.2
Extension Treatment Period (Stage 3)............................................................................21
4
SUBJECT SELECTION AND PARTICIPATION............................................................24
4.1
Number of Subjects.........................................................................................................24
4.2
Inclusion Criteria ............................................................................................................24
4.2.1
Inclusion in Stage 3..........................................................................................25
4.3
Exclusion Criteria ...........................................................................................................25
4.4
Subject Withdrawal Criteria ...........................................................................................28
4.4.1
Events Necessitating Withdrawal from Study.................................................28
4.4.2
Re-screening of Subjects..................................................................................29
5
TREATMENTS AND TREATMENT PLAN .....................................................................29
5.1
Treatments Administered................................................................................................30


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 10 of 72
Protocol v4.0, Amendment 2
03 March 2015
5.1.1
Identification of Investigational Product .........................................................30
5.1.2
Packaging and Labeling...................................................................................30
5.1.3
Storage, Accountability, and Stability.............................................................31
5.2
Dose Regimen.................................................................................................................31
5.2.1
Selection of Doses in Study.............................................................................31
5.2.2
Selection and Timing of Dose for Each Subject..............................................32
5.2.3
Subjects Who Achieve PN/I.V. Independence ................................................32
5.2.4
Compliance with Dosing Regimens.................................................................33
5.3
Prior and Concomitant Medications ...............................................................................33
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................33
6.1
Efficacy Evaluations.......................................................................................................33
6.2
Safety Evaluations ..........................................................................................................34
6.2.1
Adverse Events ................................................................................................34
6.2.2
Serious Adverse Events ...................................................................................37
6.2.3
Pregnancy Reporting........................................................................................40
6.2.4
Laboratory Evaluations....................................................................................40
6.2.5
Plasma Citrulline..............................................................................................42
6.2.6
Women of Child Bearing Potential..................................................................42
6.2.7
48-Hour Oral Fluid Intake and Urine Output ..................................................42
6.2.8
Clinical Assessment of Crohn’s Disease Activity ...........................................43
6.2.9
Subject Diaries.................................................................................................43
6.2.10
Changes in PN/I.V. Volume ............................................................................43
6.2.11
Medical History and Demographics ................................................................44
6.2.12
Concomitant Medication Assessment..............................................................44
6.2.13
Physical Examinations.....................................................................................44
6.2.14
Vital Signs and Body Weight ..........................................................................44
6.2.15
Electrocardiograms ..........................................................................................44
6.2.16
Gastrointestinal-specific Testing .....................................................................45
6.3
Pharmacokinetic Evaluations..........................................................................................45
6.4
Schedule of Evaluations and Procedures........................................................................46
7
DATA MANAGEMENT.......................................................................................................53
7.1
Data Collection ...............................................................................................................53


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 11 of 72
Protocol v4.0, Amendment 2
03 March 2015
7.2
Record Retention ............................................................................................................54
7.3
Quality Control ...............................................................................................................54
8
STATISTICAL METHODOLOGY.....................................................................................55
8.1
Demographic and Baseline Variables.............................................................................55
8.2
Efficacy and Pharmacodynamic Variables .....................................................................55
8.2.1
Efficacy and Pharmacodynamics – Stage 2.....................................................55
8.2.2
Efficacy and Pharmacodynamics – Stage 3.....................................................57
8.3
Safety ..............................................................................................................................57
8.3.1
Statistical Methods for Safety Variables..........................................................57
8.4
Pharmacokinetic Variables – Stage 2 Only ....................................................................57
8.5
Analysis Populations, Data Sets, and Time Points .........................................................57
8.5.1
Analysis Populations........................................................................................57
8.6
Statistical/Analytical Issues ............................................................................................58
8.6.1
Adjustments for Covariates..............................................................................58
8.6.2
Handling of Dropouts or Missing Data............................................................58
8.6.3
Interim Analyses ..............................................................................................58
8.6.4
Multiple Comparisons/Multiplicity .................................................................58
8.6.5
Use of an Efficacy Subset of Subjects.............................................................58
8.6.6
Examination of Subgroups...............................................................................58
8.7
Determination of Sample Size ........................................................................................58
8.8
Changes to Planned Statistical Analyses ........................................................................59
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................59
9.1
Declaration of Helsinki and Ethical Review...................................................................59
9.2
Subject Information and Consent....................................................................................59
9.3
Subject Data Protection...................................................................................................60
9.4
Payment and Compensation............................................................................................60
9.5
Changes to the Protocol ..................................................................................................60
9.6
Confidentiality/Publication of the Study ........................................................................61
9.7
Study Termination ..........................................................................................................61
10 REFERENCES.......................................................................................................................62


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 12 of 72
Protocol v4.0, Amendment 2
03 March 2015
APPENDIX 1:
PN/I.V. OPTIMIZATION.............................................................................63
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2).............................................................................................................65
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3) .................................................................................69
APPENDIX 4:  PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE......72




Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 14 of 72
Protocol v 4.0, Amendment 2
03 March 2015
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NPS
NPS Pharmaceuticals, Inc.
PI
Principal Investigator
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 15 of 72
Protocol v4.0, Amendment 2
03 March 2015
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
PN/I.V.
Parenteral Nutrition/Intravenous (volume)
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SMT
Safety Management Team
SUSAR
Suspected, unexpected, serious, adverse reaction
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 16 of 72
Protocol v4.0, Amendment 2
03 March 2015
1
INTRODUCTION
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 17 of 72
Protocol v4.0, Amendment 2
03 March 2015
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats. In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 18 of 72
Protocol v4.0, Amendment 2
03 March 2015
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.
Clinical Studies
Results of the pivotal study filed for the US New Drug Application, CL0600-020, showed that 
teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing 
parenteral nutrition/intravenous (PN/I.V.) volume in adult subjects with SBS.  In this study the 
responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects achieving a 
mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and in the United States (US).  The clinical 
profile and issues related to SBS and PN/I.V. in Japan are similar to those in the EU and in the 
US.    Therefore, there is an unmet medical need for Japanese patients with PN-dependent SBS.  
This study is designed to provide evidence of safety and efficacy of teduglutide in a Japanese 
SBS patient population. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 19 of 72
Protocol v4.0, Amendment 2
03 March 2015
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
2
OBJECTIVES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period followed by a 
long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 20 of 72
Protocol v4.0, Amendment 2
03 March 2015
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3
For Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes 
in days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment 
(Baseline/Day 0). Samples for PK analysis will be collected and recorded pre-dose, at 15, 30 and 
60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
2.4
Safety Objectives
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done during the stabilization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(Stage 3).  For all subjects with a history of Crohn’s disease, an upper GI contrast series with 
small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 21 of 72
Protocol v4.0, Amendment 2
03 March 2015
3
STUDY DESIGN
This will be an open-label, multicenter, 3-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stage 3).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. optimization period (if 
required); and a stabilization period that demonstrates stable PN/I.V. support for a minimum of 
4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stage 3)
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2 and will include subjects who complete the main treatment period and who are willing to 
continue teduglutide treatment.  Subjects will continue to receive teduglutide 0.05 mg/kg/day SC 
for up to an additional 24 months or until teduglutide is commercially available, whichever 
comes earlier. (After the approval of marketing authorization, the study will continue as a 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 22 of 72
Protocol v4.0, Amendment 2
03 March 2015
post-marketing clinical study to continuously provide teduglutide to the subjects until the product 
is commercially available.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 23 of 72
Protocol v 4.0, Amendment 2
03 March 2015
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V. 
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months or until 
Regulatory Approval
Stage 3


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 24 of 72
Protocol v 4.0, Amendment 2
03 March 2015
Schedules of evaluations for Stage 1, 2 and 3 can be found in Table 6-1, Table 6-2 and Table 6-3, 
respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization and treatment periods can 
be found in Appendix 1 and Appendix 2, respectively, and should be followed carefully 
throughout the study.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled during the recruitment period, 
which ends approximately 6 months after the initiation of the study.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1. Signed and dated Informed Consent Form (ICF) before any study-related procedures 
are performed
2. Men and women, 16 years of age or older at the time of signing the ICF 
3. Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/I.V. dependency prior to signature of ICF
4. For subjects with a history of Crohn’s disease, the subject should be in clinical 
remission for at least 12 weeks prior to dosing as demonstrated by clinical 
assessment, which may include procedure-based evidence of remission.
5. PN/I.V. requirement of at least 3 times per week during the week before screening 
and during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6. Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the 
start of teduglutide treatment, based upon the opinion of the investigator and approval 
by the sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b. Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time subject is 
optimized and enters stabilization
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 25 of 72
Protocol v4.0, Amendment 2
03 March 2015
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 of this study:
1. Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1. Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or 
concurrent participation in any clinical study using an experimental drug that would 
affect the safety of teduglutide
2. Previous use of native GLP-2 or human growth hormone within 6 months prior to 
screening
3. Previous use of intravenous glutamine, octreotide, GLP-1 analog , or dipeptidyl 
peptidase-IV inhibitors within 30 days prior to screening
4. Previous use of teduglutide
5. Serial transverse enteroplasty or any other bowel lengthening procedure performed 
within the past 3 months
6. Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed 
during the 6 months prior to screening
7. Subjects with inflammatory bowel disease who require chronic systemic 
immunosuppressant therapy that was introduced or changed during the last 3 months
8. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9. Radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening
11. Major GI surgical intervention within 3 months prior to screening (insertion of 
feeding tube or endoscopic procedure is allowed)
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell 
carcinoma within 5 years
14. Active clinically significant pancreatic or biliary disease


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 26 of 72
Protocol v4.0, Amendment 2
03 March 2015
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, 
bowel obstruction, severe water-electrolyte disturbances) within12 months prior to 
screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment at time of stabilization:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b. Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function at time of stabilization:
a.
Serum creatinine ≥2 times ULN
b. Creatinine clearance < 50 mL/minute*
*Only applies to subjects with a known history of creatinine clearance (CrCl) 
< 50 mL/min who then will be required to have a CrCl ≥ 50 mL in order to participate 
in the study.  If a CrCl cannot be measured, an estimated glomerular filtration rate 
(eGFR) may be calculated.
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results at 
time of stabilization including:
a.
Serum amylase level ≥2 times ULN
b. Serum lipase level ≥2 times ULN
20. Pregnant or lactating women
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years 
or older and/or at least 2 years had elapsed since her last menses) or who are not 
using medically acceptable methods of birth control during and for 30 days after the 
treatment period
22. Not capable of understanding or not willing to adhere to the study visit schedule and 
other protocol requirements
23. Evidence of untreated intestinal obstruction or clinically significant active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevented completion of the study, or interfered with analysis of the study 
results
25. Presence of any of the excluded disease states described in Table 4-1.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 27 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue 
due to radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the 
last 3 months
Crohn’s disease or other diseases that require biological therapy (eg, 
anti-tumor necrosis factor or natalizumab) that was introduced or 
changed in the last 6 months
Untreated known pre-malignant or malignant change in upper or 
lower GI biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile 
polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada syndrome, 
Eversmeyerous polypius)
Intestinal or other major surgery scheduled within the time frame of 
the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency 
syndrome, severe combined immunodeficiency), hypersensitivity or 
allergies to teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or 
central nervous system)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 28 of 72
Protocol v4.0, Amendment 2
03 March 2015
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 
procedures described in Section 6.2.1.2. As far as possible, all examinations scheduled for the 
end-of-study evaluations must be performed on all subjects who participate, but do not complete 
the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere with 
analysis of the study results (ie, compromise PN/I.V.):
      o Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that would put
the subject at any undue risk or prevent completion of the study
o Major surgical interventions (eg, abdominal, vascular)
o Crohn’s disease flare up
o Use of any excluded medication
o Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/ Sponsor decision (ie. subject non-compliance with study procedures)


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 29 of 72
Protocol v4.0, Amendment 2
03 March 2015

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of NPS. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.
5
TREATMENTS AND TREATMENT PLAN
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the dosing period is in
Appendix 2.
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2.  In Stage 3, subjects can continue teduglutide treatment if deemed appropriate by the 
investigator.  During the extension, the PN/I.V. dosage will be adjusted as described in 
Appendix 3.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 24 months or 
until regulatory approval and commercial availability of teduglutide in Japan.  (After the 
approval of marketing authorization, the study will continue as a post-marketing clinical study 
until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during Stage 2 or 3) will continue to receive teduglutide treatment.  If 
a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 30 of 72
Protocol v4.0, Amendment 2
03 March 2015
5.1
Treatments Administered
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen.
5.1.1
Identification of Investigational Product
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.
Active ingredient:
teduglutide
Added ingredients:
L-histidine, mannitol, monobasic and dibasic sodium 
phosphate
Route of administration:
SC injection
Dose:
0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and In-Country Clinical Caretaker name and address. All medication supplied to be 
used in this study will be manufactured, tested, labeled, and released according to current legal 
requirements and Good Manufacturing Practice.  Ancillary supply kits containing the following 
will also be provided with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution

Syringes with needles for injection (dosing)

Alcohol swabs


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 31 of 72
Protocol v4.0, Amendment 2
03 March 2015
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 32 of 72
Protocol v4.0, Amendment 2
03 March 2015
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets and the study reference manual. Each day, the 
injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.
Dosing must be performed at least 14 hours prior to antibody testing, which will be performed at 
Baseline and at Weeks 12 and 24 during Stage 2 and at Months 6, 12, 18, and 24 or early 
termination during Stage 3, or at early termination.
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues.
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  A subject will be considered to have achieved independence from PN/I.V. 
(completely weaned off PN) if the investigator prescribes no PN and there is no use of PN 
recorded in the subject diary at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 33 of 72
Protocol v4.0, Amendment 2
03 March 2015
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded in the appropriate sections of the CRF.
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, warfarin, psychotropics, and digoxin), so consideration should be given 
to modifying concomitant medication regimens.  Down-titration of concomitant medication 
dosages should be considered when drugs, including those with a narrow therapeutic range, are 
given, especially if given at dosages that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stage 3) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 and 3 of this study are given in 
Appendix 2 and Appendix 3, respectively.
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 34 of 72
Protocol v4.0, Amendment 2
03 March 2015

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes in 
days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP.  Samples for antibody analysis will be drawn at the start 
of treatment and at the EOT visit (prior to the administration of teduglutide and at least 
14 hours after the previous dose).  A 6-month follow-up is planned for any subjects testing 
positive for teduglutide-specific antibodies following the last dose of study drug.

Changes in urine output (48-hour oral fluid intake/urine output)

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 35 of 72
Protocol v4.0, Amendment 2
03 March 2015
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 36 of 72
Protocol v4.0, Amendment 2
03 March 2015
Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form.  This information will be shared 
with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF through the last dose of study drug.  Adverse events that are not resolved at 
the end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility 

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 37 of 72
Protocol v4.0, Amendment 2
03 March 2015
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s 
medical history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form.  An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug will be captured and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 38 of 72
Protocol v4.0, Amendment 2
03 March 2015
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
enter the SAE information into the SAE reporting system and fax supplemental data (eg, medical 
records or laboratory values, if applicable) to the sponsor. This ensures timely reporting of 
applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
The sponsor or designee will provide a FAX cover sheet for the investigators in the study 
reference manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 39 of 72
Protocol v4.0, Amendment 2
03 March 2015
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect study 
product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related) 

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the study reference manual.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not reported in the clinical safety section of the Investigator Brochure (IB) or if the event is of 
greater frequency, specificity, or severity than is mentioned in the IB.  The investigator will 
receive a copy of the current valid version of the IB prior to the start of the study; however, the 
investigator will not be required to assess expectedness, nor should expectedness impact the 
investigator reporting SAEs within the timeframe herein defined.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 40 of 72
Protocol v4.0, Amendment 2
03 March 2015
Upon receiving such notices, the investigator must review and retain the notice.  If it is 
determined that there is an unanticipated signal, the NPS SMT will analyze the data and prepare 
a summary supporting the determination and interpretation of the findings.  The sponsor or 
designee will send this summary to the investigators with instructions to provide it to their
Institutional Review Board (IRB).
The investigator should also comply with the IRB procedures for reporting any other safety 
information (ie, autopsy reports).  
NPS Pharmaceuticals, Inc. or its designee will be responsible for submitting SUSAR reports to 
the appropriate health authorities.  These reports will be submitted within the expedited 
timeframe.
6.2.3
Pregnancy Reporting
In the event a subject becomes pregnant during the study, study drug will be discontinued and an 
SAE form will be completed to capture potential drug exposure during pregnancy. This will be 
reported within 24 hours of becoming aware of the pregnancy. The subject will be followed up 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
[miscarriage], voluntary abortion, or therapeutic abortion). If a pregnant subject also experiences 
an SAE, an additional SAE form will be completed and submitted within 24 hours as discussed 
above. 
In the event a female partner of a male subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator (PI) and a supplemental SAE form will be completed to 
capture the event.
6.2.4
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
The site’s clinical laboratory will centrifuge and send the samples to the central lab, SRL 
Medisearch Inc. to be analyzed. Citrulline, antibody, and PK samples will be handled according 
to procedures specified in the laboratory manual.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 41 of 72
Protocol v4.0, Amendment 2
03 March 2015
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs, if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2, and Table 6-3.
Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 
Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; total, direct, and indirect bilirubin; blood 
urea nitrogen; calcium; chloride; total-cholesterol; C-reactive protein; creatinine; creatinine 
clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; potassium; 
sodium; triglycerides; and uric acid
Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  
Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)
Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 or early termination during Stage 2 of the study, and at Months 6, 12, 
18, and 24 or early termination during Stage 3.
If teduglutide-specific antibodies are detected, subjects may remain in study and will continue to 
be tested at each visit, as long as there are no concurrent AEs associated with immunogenicity.  
Subjects who test positive for teduglutide-specific antibodies at the end of Stage 2 will be 
allowed to enter Stage 3, as long as there are no concurrent AEs associated with 
immunogenicity.  The presence of teduglutide-specific antibodies will continue to be monitored 
at every visit until the end of this study.  If, at the final visit, the subject is still positive for 
teduglutide-specific antibodies, the subject will require follow-up blood draws as specified 
above. If any subject (previously negative for teduglutide antibodies) has specific 
anti-teduglutide antibodies at the final visit of this study, they will have follow-up blood draws 
for antibodies at Months 2, 3 and 6 post-study.  These may be done at a local laboratory


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 42 of 72
Protocol v4.0, Amendment 2
03 March 2015
convenient to the subject, however all blood samples will be mailed to the central laboratory for 
analysis.  If a subject’s results are negative at 2 successive visits within this time, follow-up may 
be terminated.  If at the end of 6 months the subject is still determined to have 
teduglutide-specific antibodies, the PI and the sponsor will determine if additional follow-up 
may be required.  During this follow-up, subjects will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilence database.  Collection of AE 
and/or SAE information may be done via telephone contact. 
Teduglutide Concentrations
Teduglutide concentrations will be determined in the blood samples collected for antibody 
testing, ie, at Baseline and at Weeks 12, 24 or early termination during Stage 2 of the study, and 
at Months 6, 12, 18, and 24 or early termination during Stage 3.
6.2.5
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2 and Table 6-3).  If peripheral venous access 
is not possible, blood samples for citrulline may be drawn from a central line.  The samples will 
be processed according to instructions in the laboratory manual.
6.2.6
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.7
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 43 of 72
Protocol v4.0, Amendment 2
03 March 2015
Stages 1 and 2 and at the visits specified in Table 6-3 during Stage 3. The center staff will 
contact the subject at least 48 hours before the scheduled visits to remind the subject to start 
measuring complete I/O, and to record these measurements into the diary.  At these times of 
48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at any required interim safety visit.
6.2.8
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 2 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.9
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
screening, optimization and stabilization periods, and the treatment periods in Stages 2 and 3 of 
the study.  Diaries should be distributed initially at the time the subject signs consent. Subjects 
should be instructed to record the 48-hour oral intake/urinary output prior to the screening visit 
(Visit 1.0) in order to assess their eligibility for stabilization.
6.2.10
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the PN/I.V. volume is adjusted as a result of a TEAE that 
is not related to study drug, then the diary data will not be included in the data analysis. If the 
subject has a TEAE that prevents him or her from adhering to study requirements, including 
PN/I.V. volume adjustments, the subject may be withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 and 3 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 44 of 72
Protocol v4.0, Amendment 2
03 March 2015
6.2.11
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.
6.2.12
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each visit and the details of any medications and changes therein (change in medication or 
dosage of medication) will be recorded on the CRF.
6.2.13
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and at the final visits of Stage 2 and Stage 3.  A brief examination of the GI and cardiovascular 
systems will be made at all other study visits.  Other body systems will be examined as clinically 
indicated.
6.2.14
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, and Table 6-3). Vital signs will include systolic and diastolic blood pressure 
(mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been sitting for 
5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded at 
screening and at the initial visits of Stages 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.15
Electrocardiograms
A 12-lead ECG will be performed during screening, at baseline, Week 4, and at the final visit
during Stage 2, and at the first visit (last visit for Stage 2) and at Months 2, 6, 12, 18, and 24 or 
early termination during Stage 3.  The ECG will be done at the study center after the subject has 
been resting for at least 5 minutes.  Results will include general findings only (normal/abnormal).  
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 45 of 72
Protocol v4.0, Amendment 2
03 March 2015
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.
6.2.16
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1 , Table 6-2, and Table 6-3) for details and scheduling.
6.2.16.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2 and at the end of teduglutide 
exposure in Stage 3.  A colonoscopy is required at the beginning of the study, at the end of the 
main treatment period and at the end of the study to determine if any clinically significant 
changes have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a 
subject had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.
6.2.16.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0)
in Stage 2 of the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 
minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified.
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 46 of 72
Protocol v4.0, Amendment 2
03 March 2015

CL/F

V/F
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures – Stage 3, 
Table 6-3.
Subjects who drop out of the study prior to the final visit should have all end-of-study procedures 
done. 






Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 49 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
Eligibility criteria
X
Crohn’s disease assessmentc
X
Physical examinationd
X
X
X
X
X
X
X
X
Evaluation of PN/I.V.
Xe
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Colonscopy/
  Sigmoidoscopy
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
Xf
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrulline
X
X
X
X
X
Teduglutide concentration 
and antibodies to 
teduglutide and E. coli
protein
X
X
X
PK sampling
Xj
(X)
(X)
(X)
(X)
(X)
Urine pregnancy test
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety evaluation
[X] g, h
[X]g
[X]g
[X]g
[X]g
[X]g
48-hour oral fluid intakei
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputi
(Diary)
X
X
X
X
X
X
X
X
Diary
X
X
X
X
X
X
X
X
X
Teduglutide dosingk
X
X
X
X
X
X
X
X
X
Compliancel
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 50 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
(X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous (volume); V = visit
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone.
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance.
c Subjects with active Crohn’s disease are excluded from the study participation, therefore endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion  of active disease.
d A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit.
e The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
f This is the second of 2 body weight measurements that will be used to determine drug volume.
g Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
h At the Visit 4/Week 2 interim safety visit, laboratory evaluations and 48-hour I/O are not required.  These will be assessed only if the PN/I.V. adjustment was 
tolerated.
i All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.
j Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7. The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) 
must be specified.
k Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will then self-inject the study drug at home.
l Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 51 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First Visita 
(last visit
for 
Stage 2)
Mo 
1/13b
Mo 
2/14
Mo
3/15 b
Mo 
4/16 
Mo 
5/17 b
Mo 
6/18
Mo 
7/19 b
Mo 
8/20
Mo 
9/21 b
Mo 
10/22
Mo 
11/23 b
Mo 
12
Final    
(Mo 24) 
(or 
early 
termi-
nation)
Visit Number:
V1
V2/
14
V3/ 
15
V4/ 
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/ 
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days)
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Eligibility, Informed consent
X
Medical history, demographics
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
X
X
X
X
X
X
X
X
Height
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
12-lead ECG
X
Xg
X
X
X
Colonoscopy/sigmoidoscopy 
of remnant colon
X
Citrulline
X
X
X
X
X
X
X 
X
Teduglutide concentration and 
antibodies to teduglutide and 
E. coli protein
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety visit
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
[X]d
Diary e
X
X
X
X
X
X
X
X
48-hour oral fluid intakef 
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputf (Diary)
X
X
X
X
X
X
X
X


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 52 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Evaluation of PN/I.V. (actual 
volume L/week)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
[X ] = Possible interim safety evaluation time point (Refer to footnote “d”.); BMI = body mass index; ECG = electrocardiogram; L = liter; Mo = month; PN/I.V. = parenteral 
nutrition/intravenous (support); V = visit
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the Month 1 visit.  Interim 
(standard of care) visits may be utilized to assess sunjects’ well-being (ie, occurrence of adverse events) and to check for any changes in medications.
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed appropriate.
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone.
c Full physical examination to be performed at first and final visit; a brief examination will be performed at all other study visits.
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  Hematocrit, serum blood urea 
nitrogen and serum creatinine, and urine sodium will be measured.
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The measurements should include 
1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily.
g An ECG will be taken at Visit 3, but not at Visit 15.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 53 of 72
Protocol v 4.0, Amendment 2
03 March 2015
7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s CRF by the investigational site 
staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case of 
computerized source data, the investigator has to give the sponsor access to the subject files at 
each monitoring visit. To ensure that data have been entered correctly on the CRF, they will be 
100% source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding any questions or discrepant data. The investigator or designee will be 
responsible for the timely recording of subject data into the CRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The PI or designee will review all CRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will sign the CRF via an electronic signature. The PI
will be responsible for reviewing the data in a timely manner.  Non-CRF data will be sent to the 
sponsor or designee via a data transfer from the appropriate vendor for assimilation into the 
database. Paper copies non-CRF data will be signed and dated by the investigator and filed.
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with CRF guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that should 
be resolved at the study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 54 of 72
Protocol v4.0, Amendment 2
03 March 2015
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.
An audit will be performed by the Data Management group. When all issues from the audit are 
resolved, and all data management processes are completed for finalizing the database, the 
database will be ready for statistical analysis by NPS or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC. In the event that the appropriate individual at the site provides an 
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 55 of 72
Protocol v4.0, Amendment 2
03 March 2015
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.
8
STATISTICAL METHODOLOGY 
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 56 of 72
Protocol v4.0, Amendment 2
03 March 2015

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the LS mean percent change in weekly 
PN/I.V. volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the 
placebo group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, 
PN/I.V. results will be compared with those from Study CL0600-020.  The comparison 
should take into account the anticipated variability of the data due to the small number of 
subjects in Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95%
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with those 
from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should take 
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 57 of 72
Protocol v4.0, Amendment 2
03 March 2015
8.2.2
Efficacy and Pharmacodynamics – Stage 3
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.
8.3
Safety
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, laboratory safety data, antibodies to teduglutide, and changes in urine 
output, body weight, and BMI.  See Section 6.2 for a full list of safety variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg., number and percentage of subjects) for each treatment group. Adverse 
events will be summarized by severity, relationship to treatment, AEs leading to discontinuation, 
and AEs leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point for each treatment group. 
The number and percentage of subjects classified as having antibodies to teduglutide will be used to 
summarize the presence of antibodies for each treatment group.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study. 
The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow up. The primary population analyzed for 
efficacy will be the ITT population. An additional per-protocol population analysis will also be 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 58 of 72
Protocol v4.0, Amendment 2
03 March 2015
performed as secondary/sensitivity analysis. Detailed per-protocol evaluable definitions will be 
documented in the Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 59 of 72
Protocol v4.0, Amendment 2
03 March 2015
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
NPS SMT has assessed it as an unanticipated problem.  Approval for protocol amendments will 
be transmitted in writing to the investigator.
The investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed one year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject. A subject information/ICF model will be provided by the 
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 60 of 72
Protocol v4.0, Amendment 2
03 March 2015
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods. The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial. IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 61 of 72
Protocol v4.0, Amendment 2
03 March 2015
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 62 of 72
Protocol v4.0, Amendment 2
03 March 2015
10
REFERENCES
None


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 63 of 72
Protocol v4.0, Amendment 2
03 March 2015
APPENDIX 1:
PN/I.V. OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 64 of 72
Protocol v4.0, Amendment 2
03 March 2015
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 
by targeted urine output of 1.0 to 2.0 L/day.  If a subject has not achieved an optimal 
tolerated volume of PN/I.V. after 8 weeks, consult the sponsor’s Medical Monitor.
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 65 of 72
Protocol v4.0, Amendment 2
03 March 2015
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD - STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to 
reduce volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Monitor.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 66 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table A2-1: PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% (Week 2) or to 
previous level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A2-2), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of stabilized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
L = liter; PN/I.V. – parenteral nutrition/intravenous (volume)
Table A2-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 67 of 72
Protocol v4.0, Amendment 2
03 March 2015
PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be collected to 
evaluate hydration and nutrition (see Table A2-2).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. (Reduction 
of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and the 
health status of the subject will be assessed after 5 to 7 days of the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.
Table A2- 3: Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is 
dehydrated (See Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not 
dehydrated, but is inadequately nourished 
(See Table A2-2)
If possible, maintain PN/I.V. volume 
and increase nutrition. If not, increase 
PN/I.V. to previous volumea
Baseline output or greater and subject is 
adequately hydrated and nourished (See 
Table A2-2)
Maintain PN/I.V.
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume).
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate increase in PN/I.V.
is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V..


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 68 of 72
Protocol v4.0, Amendment 2
03 March 2015
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  During the 
remainder of the study, subjects may undergo 1 additional attempt to reduce volume by 
at least 10%.
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 69 of 72
Protocol v4.0, Amendment 2
03 March 2015
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of OPTIMIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the NPS Medical Director.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 70 of 72
Protocol v4.0, Amendment 2
03 March 2015
Table A3- 1: PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% or to previous 
level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished 
(see Table A2-1), increase PN/I.V.  If not, 
maintain PN/I.V.
Baseline or more, and less than a 
10% increase over Baseline
Maintain PN/I.V.
At least a 10% increase over 
Baseline
Reduce PN/I.V. by at least 10% of optimized 
Baseline level up to a clinically appropriate 
amount (maximum of 30%).
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume)
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily.  All blood and urine samples should be taken at a consistent time period throughout 
the study, convenient for the subject and site staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed after 5 to 7 days of the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. Depending on the 
wellbeing of the subject it is at the discretion of the investigator to abstain from the 
laboratory safety samples.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 71 of 72
Protocol v4.0, Amendment 2
03 March 2015
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.
Table A3-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
* AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Protocol TED-C14-004
Teduglutide (rDNA origin) for injection
Page 72 of 72
Protocol v4.0, Amendment 2
03 March 2015
APPENDIX 4:
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study 
in compliance with this protocol, any future amendments, and with any other study conduct procedures 
provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practice 
(GCP) and all other applicable regulatory requirements to obtain written and dated approval from the 
Institutional or Central Review Board (IRB) or Independent Ethics Committee (IRB) for the study 
protocol and any amendments thereof, written informed consent or updates thereof, subject recruitment 
procedures (eg, advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from the 
sponsor and review and documented approval from the IRB, except to eliminate an immediate hazard to 
the study subjects, or when change(s) involves only logistical or administrative aspects of the clinical 
study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by 
the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in 
this protocol, and any other information provided by the sponsor or In-country Clinical Caretaker 
including, but not limited to, the current Investigator’s Brochure or equivalent document and approved 
product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the foreseen 
duration of the clinical study in order to conduct the study properly, ethically, and safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


TEDUGLUTIDE (ALX-0600)
A 3-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 5.0
Phase 3
Sponsor:  
NPS Pharmaceuticals, Inc.*
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
USA
(*NPS was acquired by Shire, Inc. on 21 February 2015)
Medical Monitor (Medical Expert of the Sponsor):
 MD
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-23 Shimomiyabicho, Shinjuku-ku,
Tokyo 162-0822, Japan
TEL:
FAX:
Protocol v1.0:
05 August 2014
Protocol v2.0, Amendment 1:
20 August 2014 (administrative amendment)
Protocol v3.0, Amendment 1 (corrected): 15 September 2014
Protocol v4.0, Amendment 2:
03 March 2015
Protocol v5.0, Amendment 3:
17 November 2015
The information contained in this document is the property of the sponsor. It is understood that the 
information will not be disclosed to others aside from the investigator(s) and duly designated staff, 
applicable IRB(s) and regulatory authorities without prior written approval from the sponsor, except to 
the extent necessary to obtain informed consent from those persons to whom the study drug may be 
administered.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 2 of 72
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the 
sponsor’s Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) 
Required by the Protocol Form within 24 hours to the sponsor’s Global Pharmacovigilance 
and Risk Management Department. Applicable fax numbers and e-mail address can be found 
on the form (sent under separate cover) and below. A copy of this form must also be sent to 
the sponsor’s Medical Monitor by fax or e-mail using the details below.
Global Pharmacovigilance and Risk Management
E-mail: 
Fax:
 MD
Fax:
E-mail:


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 3 of 72
SUMMARY
Protocol TED-C14-004
Title of Study: A 3-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 3-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous volume (PN/I.V.) support optimization period (if 
required); and a stabilization period in which stable administration of PN/I.V. support, defined 
as a targeted urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and 
nourished, is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a 
subject fails to remain stable for at least 4 consecutive weeks, the subject may start the 
optimization period again, beginning with Visit 1.1. Those subjects who fail to stabilize after 
2 attempts will not proceed further and will not be dosed. Stage 2 will be a dosing period of 
24 weeks, during which subjects will self-administer the study drug at home.
Stage 3 is the long-term extension portion of the study, which will begin immediately 
following Stage 2.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 
24 months or until regulatory approval and commercial availability of teduglutide in Japan. 
(After the approval of marketing authorization, the study will continue as a post-marketing 
clinical study until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled during the recruitment 
period, which ends approximately 6 months after the initiation of the study.
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 4 of 72

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:
o
Actual PN/I.V. usage matches prescribed PN/I.V.
o
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.
o
Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function at the time of stabilization: 
o
Total bilirubin < 2 times upper limit of normal (ULN)
o
Aspartate aminotransferase (AST) < 5 times ULN
o
Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function at the time of stabilization:
o
Serum creatinine < 2 times ULN
o
Creatinine clearance ≥50 mL/minute (only in subjects with a known history of 
creatinine clearance < 50 mL/min)

Adequate pancreatic function at the time of stabilization:
o
Serum amylase < 2 times ULN
o
Serum lipase < 2 times ULN

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 5 of 72

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC)
injection is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile 
water for injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study.
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen or either thigh or arm. The first SC injection should be administered under the 
supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period (if required); and a stabilization period that demonstrates stable 
administration of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks
(total maximum 16 weeks for optimization/stabilization periods).  Subjects who fail 
optimization may repeat this period (taking up to an additional 16 weeks).  Therefore the total 
possible duration of Stage 1 is up to 33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue in the extension 
treatment period for up to an additional 24 months (Stage 3) or until teduglutide is 
commercially available, whichever comes first. (After the approval of marketing 
authorization, the study will continue as a post-marketing clinical study in order to 
continuously provide teduglutide to the subjects until the product is commercially available).
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 6 of 72
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stage 3:  Absolute and percent change from baseline in 
weekly PN/I.V. volume and changes in days per week of PN/I.V. support and plasma 
citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose PK will be evaluated on the first day of 
teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected and 
recorded pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours 
post-dose.
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 7 of 72
Safety:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory 
safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and changes in 
48-hour urine output, body weight and body mass index (BMI) will be evaluated.  An 
abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will be done during 
the stabilization period if these procedures were not done in the 6 months prior to screening.  
Colonoscopy/sigmoidoscopy will be repeated at the end of the main treatment period 
(Stage 2) and at the end of the extension treatment period (Stage 3).  For all subjects with a 
history of Crohn’s disease, an upper gastrointestinal (GI) contrast series with small bowel 
follow-through will be performed during the stabilization period, prior to the baseline visit.
Statistical methods:  No formal testing will be conducted for efficacy or pharmacodynamic 
variables.  For continuous variables, descriptive statistics will be used to summarize median, 
maximum, minimum, mean (± standard deviation [SD]), geometric mean (± standard error
[SE]) and its 95% confidence interval.  For categorical variables, n (%) will be summarized.  
Individual data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the 
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.




Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 9 of 72
TABLE OF CONTENTS
EMERGENCY CONTACT INFORMATION ...........................................................................2
SUMMARY ....................................................................................................................................3
SIGNATURE PAGE......................................................................................................................8
TABLE OF CONTENTS ..............................................................................................................9
LIST OF TABLES AND FIGURES...........................................................................................13
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................14
1
INTRODUCTION..................................................................................................................16
1.1
Background.....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design.............................................................................................18
2
OBJECTIVES ........................................................................................................................19
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2 ....................................................19
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3 ....................................................20
2.3
Pharmacokinetic Endpoints – Stage 2 Only....................................................................20
2.4
Safety Objectives ............................................................................................................20
3
STUDY DESIGN....................................................................................................................21
3.1
Main Treatment Period (Stages 1 and 2) ........................................................................21
3.2
Extension Treatment Period (Stage 3)............................................................................21
4
SUBJECT SELECTION AND PARTICIPATION............................................................24
4.1
Number of Subjects.........................................................................................................24
4.2
Inclusion Criteria ............................................................................................................24
4.2.1
Inclusion in Stage 3..........................................................................................25
4.3
Exclusion Criteria ...........................................................................................................25
4.4
Subject Withdrawal Criteria ...........................................................................................28
4.4.1
Events Necessitating Withdrawal from Study.................................................29
4.4.2
Re-screening of Subjects..................................................................................29
5
TREATMENTS AND TREATMENT PLAN .....................................................................30
5.1
Treatments Administered................................................................................................30
5.1.1
Identification of Investigational Product .........................................................30


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 10 of 72
5.1.2
Packaging and Labeling...................................................................................31
5.1.3
Storage, Accountability, and Stability.............................................................31
5.2
Dose Regimen.................................................................................................................32
5.2.1
Selection of Doses in Study.............................................................................32
5.2.2
Selection and Timing of Dose for Each Subject..............................................32
5.2.3
Subjects Who Achieve PN/I.V. Independence ................................................33
5.2.4
Compliance with Dosing Regimens.................................................................33
5.3
Prior and Concomitant Medications ...............................................................................33
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................34
6.1
Efficacy Evaluations.......................................................................................................34
6.2
Safety Evaluations ..........................................................................................................34
6.2.1
Adverse Events ................................................................................................35
6.2.1.1
Adverse Event Definition .................................................................35
6.2.1.2
Procedures for Reporting Adverse Events........................................37
6.2.2
Serious Adverse Events ...................................................................................38
6.2.2.1
Serious Adverse Event Definition ....................................................38
6.2.2.2
Procedures for Reporting Serious Adverse Events...........................39
6.2.3
Pregnancy Reporting........................................................................................42
6.2.4
Laboratory Evaluations....................................................................................42
6.2.5
Plasma Citrulline..............................................................................................43
6.2.6
Women of Child Bearing Potential..................................................................44
6.2.7
48-Hour Oral Fluid Intake and Urine Output ..................................................44
6.2.8
Clinical Assessment of Crohn’s Disease Activity ...........................................44
6.2.9
Subject Diaries.................................................................................................44
6.2.10
Changes in PN/I.V. Volume ............................................................................45
6.2.11
Medical History and Demographics ................................................................45
6.2.12
Concomitant Medication Assessment..............................................................45
6.2.13
Physical Examinations.....................................................................................45
6.2.14
Vital Signs and Body Weight ..........................................................................45
6.2.15
Electrocardiograms ..........................................................................................46
6.2.16
Gastrointestinal-specific Testing .....................................................................46
6.2.16.1 Colonoscopy/Sigmoidoscopy ...........................................................46


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 11 of 72
6.2.16.2 Abdominal Ultrasound and Upper GI Contrast Series with Small 
Bowel Follow-through......................................................................47
6.3
Pharmacokinetic Evaluations..........................................................................................47
6.4
Schedule of Evaluations and Procedures........................................................................47
7
DATA MANAGEMENT.......................................................................................................54
7.1
Data Collection ...............................................................................................................54
7.2
Record Retention ............................................................................................................55
7.3
Quality Control ...............................................................................................................55
8
STATISTICAL METHODOLOGY.....................................................................................56
8.1
Demographic and Baseline Variables.............................................................................56
8.2
Efficacy and Pharmacodynamic Variables .....................................................................56
8.2.1
Efficacy and Pharmacodynamics – Stage 2.....................................................56
8.2.2
Efficacy and Pharmacodynamics – Stage 3.....................................................57
8.3
Safety ..............................................................................................................................58
8.3.1
Statistical Methods for Safety Variables..........................................................58
8.4
Pharmacokinetic Variables – Stage 2 Only ....................................................................58
8.5
Analysis Populations, Data Sets, and Time Points .........................................................58
8.5.1
Analysis Populations........................................................................................58
8.6
Statistical/Analytical Issues ............................................................................................58
8.6.1
Adjustments for Covariates..............................................................................58
8.6.2
Handling of Dropouts or Missing Data............................................................59
8.6.3
Interim Analyses ..............................................................................................59
8.6.4
Multiple Comparisons/Multiplicity .................................................................59
8.6.5
Use of an Efficacy Subset of Subjects.............................................................59
8.6.6
Examination of Subgroups...............................................................................59
8.7
Determination of Sample Size ........................................................................................59
8.8
Changes to Planned Statistical Analyses ........................................................................59
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................59
9.1
Declaration of Helsinki and Ethical Review...................................................................59
9.2
Subject Information and Consent....................................................................................60
9.3
Subject Data Protection...................................................................................................60


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 12 of 72
9.4
Payment and Compensation............................................................................................61
9.5
Changes to the Protocol ..................................................................................................61
9.6
Confidentiality/Publication of the Study ........................................................................61
9.7
Study Termination ..........................................................................................................62
10 REFERENCES.......................................................................................................................63
APPENDIX 1:
PN/I.V. OPTIMIZATION.............................................................................64
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD – STAGE 2)............................................................................................................66
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3) .................................................................................69
APPENDIX 4:  PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE......72


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 13 of 72
LIST OF TABLES AND FIGURES
Table 4-1
Excluded Diseases and Illnesses..........................................................................27
Table 6-1
Schedule of Evaluations and Procedures – Stage 1...........................................48
Table 6-2
Schedule of Evaluations and Procedures – Stage 2...........................................50
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)......................52
Figure 3-1
Study Diagram .....................................................................................................23


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 14 of 72
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 
PN/I.V.
Parenteral Nutrition/Intravenous (volume)


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 15 of 72
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SUSAR
Suspected, unexpected, serious, adverse reaction
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 16 of 72
1
INTRODUCTION
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 17 of 72
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats.  In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 18 of 72
Clinical Studies
Results of the pivotal study filed for the United States (US) New Drug Application, CL0600-020, 
showed that teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo 
in reducing parenteral nutrition/intravenous (PN/I.V.) volume in adult subjects with SBS.  In this 
study the responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects 
achieving a mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and the US.  The clinical profile and issues 
related to SBS and PN/I.V. in Japan are similar to those in the EU and US.  Therefore, there is an 
unmet medical need for Japanese patients with PN-dependent SBS.  This study is designed to 
provide evidence of safety and efficacy of teduglutide in a Japanese SBS patient population.
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 19 of 72
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
2
OBJECTIVES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics
(PK) of teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period 
followed by a long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 20 of 72
2.2
Efficacy and Pharmacodynamic Endpoints – Stage 3
For Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes 
in days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Baseline/Day 0). 
Samples for PK analysis will be collected and recorded pre-dose, at 15, 30 and 60 minutes 
post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
2.4
Safety Objectives
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done during the stabilization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated 
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(Stage 3).  For all subjects with a history of Crohn’s disease, an upper GI contrast series with 
small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 21 of 72
3
STUDY DESIGN
This will be an open-label, multicenter, 3-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stage 3).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. optimization period (if 
required); and a stabilization period that demonstrates stable PN/I.V. support for a minimum of 
4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stage 3)
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2 and will include subjects who complete the main treatment period and who are willing to 
continue teduglutide treatment.  Subjects will continue to receive teduglutide 0.05 mg/kg/day SC 
for up to an additional 24 months or until teduglutide is commercially available, whichever 
comes earlier. (After the approval of marketing authorization, the study will continue as a 
post-marketing clinical study to continuously provide teduglutide to the subjects until the product 
is commercially available.)


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 22 of 72
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  If a subject relapses following achievement of PN/I.V. independence, 
PN/I.V. support will be re-initiated and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 23 of 72
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V. 
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months or until 
Regulatory Approval
Stage 3


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 24 of 72
Schedules of evaluations for Stage 1, 2 and 3 can be found in Table 6-1, Table 6-2 and Table 6-3, 
respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization and treatment periods can 
be found in Appendix 1 and Appendix 2, respectively, and should be followed carefully 
throughout the study.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled during the recruitment period, 
which ends approximately 6 months after the initiation of the study.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1.
Signed and dated Informed Consent Form (ICF) before any study-related procedures are 
performed
2.
Men and women, 16 years of age or older at the time of signing the ICF 
3.
Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of ICF
4.
For subjects with a history of Crohn’s disease, the subject should be in clinical remission for 
at least 12 weeks prior to dosing as demonstrated by clinical assessment, which may include 
procedure-based evidence of remission.
5.
PN/I.V. requirement of at least 3 times per week during the week before screening and 
during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6.
Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the start of 
teduglutide treatment, based upon the opinion of the investigator and approval by the 
sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b.
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall within 
± 25% of the respective 48-hour I/O volumes at the time subject is optimized and enters 
stabilization


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 25 of 72
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 of this study:
1.
Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1.
Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or concurrent 
participation in any clinical study using an experimental drug that would affect the safety of 
teduglutide
2.
Previous use of native GLP-2 or human growth hormone within 6 months prior to screening
3.
Previous use of intravenous glutamine, octreotide, GLP-1 analog, or dipeptidyl peptidase-IV 
inhibitors within 30 days prior to screening
4.
Previous use of teduglutide
5.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
the past 3 months
6.
Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed during 
the 6 months prior to screening
7.
Subjects with inflammatory bowel disease who require chronic systemic immunosuppressant 
therapy that was introduced or changed during the last 3 months
8.
Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA 
abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9.
Radiographic or manometric evidence of pseudo-obstruction or severe known dysmotility 
syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 26 of 72
11. Major GI surgical intervention within 3 months prior to screening (insertion of feeding tube 
or endoscopic procedure is allowed)
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell carcinoma 
within 5 years
14. Active clinically significant pancreatic or biliary disease
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, bowel 
obstruction, severe water-electrolyte disturbances) within 12 months prior to screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment at time of stabilization:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b.
Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function at time of stabilization:
a.
Serum creatinine ≥2 times ULN
b.
Creatinine clearance < 50 mL/minute*
*Only applies to subjects with a known history of creatinine clearance (CrCl) 
< 50 mL/min who then will be required to have a CrCl ≥ 50 mL in order to participate 
in the study.  If a CrCl cannot be measured, an estimated glomerular filtration rate 
(eGFR) may be calculated.
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results at time of 
stabilization including:
a.
Serum amylase level ≥2 times ULN
b.
Serum lipase level ≥2 times ULN
20. Pregnant or lactating women


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 27 of 72
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years or 
older and/or at least 2 years had elapsed since her last menses) or who are not using 
medically acceptable methods of birth control during and for 30 days after the treatment 
period
22. Not capable of understanding or not willing to adhere to the study visit schedule and other 
protocol requirements
23. Evidence of untreated intestinal obstruction or clinically significant active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any undue 
risk, prevented completion of the study, or interfered with analysis of the study results
25. Presence of any of the excluded disease states described in Table 4-1
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue 
due to radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 28 of 72
Table 4-1
Excluded Diseases and Illnesses
Body system or 
disease type
Known conditions excluded
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the 
last 3 months
Crohn’s disease or other diseases that require biological therapy (eg, 
anti-tumor necrosis factor or natalizumab) that was introduced or 
changed in the last 6 months
Untreated known pre-malignant or malignant change in upper or 
lower GI biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile 
polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada syndrome, 
Eversmeyerous polypius)
Intestinal or other major surgery scheduled within the time frame of 
the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency 
syndrome, severe combined immunodeficiency), hypersensitivity or 
allergies to teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or 
central nervous system)
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 29 of 72
procedures described in Section 6.2.1.2.  As far as possible, all examinations scheduled for the 
end-of-study evaluations must be performed on all subjects who participate, but do not complete 
the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere
with analysis of the study results (ie, compromise PN/I.V.):
o
Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that 
would put the subject at any undue risk or prevent completion of the study
o
Major surgical interventions (eg, abdominal, vascular)
o
Crohn’s disease flare up
o
Use of any excluded medication
o
Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/Sponsor decision (ie, subject non-compliance with study procedures)

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of the sponsor. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 30 of 72
5
TREATMENTS AND TREATMENT PLAN
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the dosing period is in
Appendix 2.
Stage 3 is the long-term extension portion of the study, which will begin immediately following 
Stage 2.  In Stage 3, subjects can continue teduglutide treatment if deemed appropriate by the 
investigator.  During the extension, the PN/I.V. dosage will be adjusted as described in 
Appendix 3.  Subjects will continue to receive teduglutide 0.05 mg/kg/day for up to 24 months or 
until regulatory approval and commercial availability of teduglutide in Japan.  (After the 
approval of marketing authorization, the study will continue as a post-marketing clinical study 
until the market launch.)
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during Stage 2 or 3) will continue to receive teduglutide treatment.  If 
a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.
5.1
Treatments Administered
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen.
5.1.1
Identification of Investigational Product
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 31 of 72
Active ingredient:
teduglutide
Added ingredients:
L-histidine, mannitol, monobasic and dibasic sodium 
phosphate
Route of administration:
SC injection
Dose:
0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and In-Country Clinical Caretaker name and address. All medication supplied to be 
used in this study will be manufactured, tested, labeled, and released according to current legal 
requirements and Good Manufacturing Practice.  Ancillary supply kits containing the following 
will also be provided with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution

Syringes with needles for injection (dosing)

Alcohol swabs
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 32 of 72
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets and the study reference manual. Each day, the 
injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 33 of 72
Dosing must be performed at least 14 hours prior to antibody testing, which will be performed at 
Baseline and at Weeks 12 and 24 during Stage 2 and at Months 6, 12, 18, and 24 or early 
termination during Stage 3, or at early termination.
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues.
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support (either during 
optimization or at any time during the Stage 2 or 3 treatment period) will continue to receive 
teduglutide treatment.  A subject will be considered to have achieved independence from PN/I.V. 
(completely weaned off PN) if the investigator prescribes no PN and there is no use of PN 
recorded in the subject diary at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded in the appropriate sections of the CRF.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 34 of 72
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, warfarin, psychotropics, and digoxin), so consideration should be given 
to modifying concomitant medication regimens.  Down-titration of concomitant medication 
dosages should be considered when drugs, including those with a narrow therapeutic range, are 
given, especially if given at dosages that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stage 3) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 and 3 of this study are given in 
Appendix 2 and Appendix 3, respectively.
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stage 3, absolute and percent change from baseline in weekly PN/I.V. volume and changes in 
days per week of PN/I.V. support and plasma citrulline levels will continue to be evaluated 
throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 35 of 72

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP (see Table 6-1, Table 6-2, and Table 6-3 for timing)

Changes in urine output (48-hour oral fluid intake/urine output)

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 36 of 72
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 37 of 72
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 6.2.1.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors unless these result in an SAE. The categories 
below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – An accidental or intentional administration of an excessive dose of a product
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF through the last dose of study drug.  Adverse events that are not resolved at 
the end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 38 of 72
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs 
usual activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required

Relationship to study drug (not related, related): identify relationship as “related” if a causal 
relationship between the investigational product and an AE is at least a reasonable possibility 

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below.

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives only 
one outcome.
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s medical 
history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form.  An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug will be captured and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 39 of 72

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of 
drug dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
All initial and follow-up SAE reports must be reported by the investigator to the sponsor’s
Global Pharmacovigilance and Risk Management Department and the CRO/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 6.2.1.1) unless they result in an SAE.
The investigator must complete, sign, and date the sponsor’s Clinical Study Serious Adverse 
Event and Non-serious AEs Required by the Protocol Form and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 40 of 72
documents are not to be sent unless requested) and fax or e-mail the form to the sponsor’s Global 
Pharmacovigilance and Risk Management Department. A copy of the sponsor’s Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and any applicable 
follow-up reports) must also be sent to the sponsor’s Medical Monitor using the details specified 
in the emergency contact information section of the protocol.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
The sponsor or designee will provide a FAX cover sheet for the investigators.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
The causality categories are:

Not related
o
Unrelated to investigational product

Possibly Related
o
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of investigational product, but which could also be explained by 
concurrent disease or other drugs or chemicals.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 41 of 72

Probably Related
o
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of investigational product, unlikely to be attributable to concurrent 
disease or other drugs and chemicals and which follows a clinically reasonable 
response on de-challenge. The association of the clinical event or laboratory 
abnormality must also have some biologic plausibility, at least on theoretical 
grounds.

Related
o
The event follows a reasonable temporal sequence from administration of the 
investigational product, follows a known or suspected response pattern to the 
investigational product, is confirmed by improvement upon stopping the 
investigational product (de-challenge), and reappears upon repeated exposure (re-
challenge). Note that this is not to be construed as requiring re-exposure of the 
patient to investigational product; however, the determination of definitely related 
can only be used when recurrence of event is observed.
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not reported in the clinical safety section of the Investigator Brochure (IB) or if the event is of 
greater frequency, specificity, or severity than is mentioned in the IB.  The investigator will 
receive a copy of the current valid version of the IB prior to the start of the study; however, the 
investigator will not be required to assess expectedness, nor should expectedness impact the 
investigator reporting SAEs within the timeframe herein defined.
The investigator should also comply with the Institutional Review Board (IRB) procedures for 
reporting any other safety information (eg, autopsy reports).  
The sponsor or its designee will be responsible for submitting SUSAR reports to the appropriate 
health authorities.  These reports will be submitted within the expedited timeframe.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 42 of 72
6.2.3
Pregnancy Reporting
In the event a subject becomes pregnant during the study, study drug will be discontinued and an 
SAE form will be completed to capture potential drug exposure during pregnancy. This will be 
reported within 24 hours of becoming aware of the pregnancy. The subject will be followed up 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
[miscarriage], voluntary abortion, or therapeutic abortion). If a pregnant subject also experiences 
an SAE, an additional SAE form will be completed and submitted within 24 hours as discussed 
above. 
In the event a female partner of a male subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator (PI) and a supplemental SAE form will be completed to 
capture the event.
6.2.4
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
The site’s clinical laboratory will centrifuge and send the samples to the central lab, SRL 
Medisearch Inc. to be analyzed.  Citrulline, antibody, and PK samples will be handled according 
to procedures specified in the laboratory manual.
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs, if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2, and Table 6-3:

Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 43 of 72

Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; total, direct, and indirect bilirubin; blood 
urea nitrogen; calcium; chloride; total-cholesterol; C-reactive protein; creatinine; creatinine 
clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; potassium; 
sodium; triglycerides; and uric acid

Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  

Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)

Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 or early termination during Stage 2 of the study, and at Months 6, 12, 
18, and 24 or early termination during Stage 3.
Antibody testing is a 3-part process. If a sample is negative, no further testing is done. If a 
sample is positive, testing is done for teduglutide-specific antibodies. If these are detected, the 
titer is derived and neutralizing antibody testing is done. Subjects may remain on treatment and 
will continue to be tested at each visit as long as there are no concurrent AEs associated with 
immunogenicity.
Subjects who test positive for teduglutide-specific antibodies at the end of Stage 2 will be 
allowed to enter Stage 3, as long as there are no concurrent AEs associated with 
immunogenicity.  The presence of teduglutide-specific antibodies will continue to be monitored 
at every visit where antibody testing is scheduled per protocol. 
6.2.5
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2 and Table 6-3).  If peripheral venous access 
is not possible, blood samples for citrulline may be drawn from a central line.  The samples will 
be processed according to instructions in the laboratory manual.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 44 of 72
6.2.6
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.7
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 
Stages 1 and 2 and at the visits specified in Table 6-3 during Stage 3. The center staff will 
contact the subject at least 48 hours before the scheduled visits to remind the subject to start 
measuring complete I/O, and to record these measurements into the diary.  At these times of 
48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at any required interim safety visit.
6.2.8
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 2 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.9
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
screening, optimization and stabilization periods, and the treatment periods in Stages 2 and 3 of 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 45 of 72
the study.  Diaries should be distributed initially at the time the subject signs consent. Subjects 
should be instructed to record the 48-hour oral intake/urinary output prior to the screening visit 
(Visit 1.0) in order to assess their eligibility for stabilization.
6.2.10
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the PN/I.V. volume is adjusted as a result of a TEAE that 
is not related to study drug, then the diary data will not be included in the data analysis. If the 
subject has a TEAE that prevents him or her from adhering to study requirements, including 
PN/I.V. volume adjustments, the subject may be withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 and 3 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.
6.2.11
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.
6.2.12
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each visit and the details of any medications and changes therein (change in medication or 
dosage of medication) will be recorded on the CRF.
6.2.13
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and at the final visits of Stage 2 and Stage 3.  A brief examination of the GI and cardiovascular 
systems will be made at all other study visits.  Other body systems will be examined as clinically 
indicated.
6.2.14
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, and Table 6-3). Vital signs will include systolic and diastolic blood pressure 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 46 of 72
(mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been sitting for 
5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded at 
screening and at the initial visits of Stages 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.15
Electrocardiograms
A 12-lead ECG will be performed during screening, at baseline, Week 4, and at the final visit
during Stage 2, and at the first visit (last visit for Stage 2) and at Months 2, 6, 12, 18, and 24 or 
early termination during Stage 3.  The ECG will be done at the study center after the subject has 
been resting for at least 5 minutes.  Results will include general findings only (normal/abnormal).  
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.
6.2.16
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1, Table 6-2, and Table 6-3) for details and scheduling.
6.2.16.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2 and at the end of teduglutide 
exposure in Stage 3.  A colonoscopy is required at the beginning of the study, at the end of the 
main treatment period and at the end of the study to determine if any clinically significant 
changes have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a 
subject had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 47 of 72
6.2.16.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0) in Stage 2 of 
the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 minutes post-
dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose. The site of teduglutide administration prior 
to PK blood draws (arm, thigh, abdomen) must be specified.
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2

CL/F

V/F
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures – Stage 3, 
Table 6-3.
Subjects who drop out of the study prior to the final visit should have all end-of-study procedures 
done. 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 48 of 72 
 
Table 6-1 
Schedule of Evaluations and Procedures – Stage 1 
Procedures 
Prior to 
screening 
Screening 
(7-day 
maximum) 
PN/I.V. Optimization Period 
(8-week maximum) 
PN/I.V. 
Stabilization 
Period 
4-8 weeks  
(± 7 days) 
Week 2  
(± 3 days) 
Week 4  
(± 3 days 
Week 6  
(± 3 days) 
Week 8 
 (± 3 days) 
Visit Number: 
 
V1.0 
V1.1 
V1.2 
V1.3 
V1.4 
V1.5 
Informed consent 
Xa 
X 
 
 
 
 
 
Eligibility criteria 
 
X 
 
 
 
 
 
Medical history, demographics 
 
X 
 
 
 
 
 
Crohn’s disease assessment 
 
X 
 
 
 
 
 
Physical examinationb 
 
X 
 
 
 
 
 
Evaluation of PN/I.V. 
 
X 
X 
X 
X 
X 
Xc 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Abdominal ultrasoundd 
 
 
 
 
 
 
X 
Upper GI contrast series with 
small bowel follow-throughe 
 
 
 
 
 
 
X 
Colonoscopy/sigmoidoscopy 
of remnant colonf 
 
 
 
 
 
 
X 
Concomitant medicationg 
 
X 
X 
X 
X 
X 
X  
Vital signs 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Body weight and BMI 
 
X 
X 
X 
X 
X 
Xh 
12-lead ECG 
 
X 
 
 
 
 
 
Safety laboratory tests 
 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
 
X 
 
 
 
 
 
Interim safety evaluation 
 
[X]i 
[X]i 
[X]i 
[X]i 
[X]i 
 
Diary 
Xa 
X 
X 
X 
X 
X 
X 
Review 48-hour oral fluid 
intakej (Diary) 
 
X 
X 
X 
X 
X 
X 
Review 48-hour urine outputj 
(Diary) 
 
X 
X 
X 
X 
X 
X 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 49 of 72 
 
Table 6-1 
Schedule of Evaluations and Procedures – Stage 1 
Procedures 
Prior to 
screening 
Screening 
(7-day 
maximum) 
PN/I.V. Optimization Period 
(8-week maximum) 
PN/I.V. 
Stabilization 
Period 
4-8 weeks  
(± 7 days) 
Week 2  
(± 3 days) 
Week 4  
(± 3 days 
Week 6  
(± 3 days) 
Week 8 
 (± 3 days) 
Visit Number: 
 
V1.0 
V1.1 
V1.2 
V1.3 
V1.4 
V1.5 
Optimization assessmentk 
 
X 
X 
X 
X 
X 
 
BMI = body mass index; ECG = electrocardiogram; GI = gastrointestinal; ICF = Informed Consent Form; PN/I.V. = parenteral nutrition/intravenous (volume); 
V = visit 
Note: One repeat of the optimization/stabilization periods combined is permitted. 
a The ICF is to be distributed to the subject for review.  Once the ICF has been signed by the subject, the diary should be given to the subject in order to record 
the 48-hour intake/output measurements.   No study-related procedures are to be performed unless the ICF has been signed. 
b A full physical examination is to be performed at screening. 
c PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.). 
d Abdominal ultrasound should be completed during the stabilization period, prior to the baseline visit if not performed within 6 months prior to screening. 
e Upper GI contrast series with small bowel follow-through is required for subjects with Crohn’s disease.  This should be completed during the stabilization 
period, prior to the baseline visit. 
f Colonoscopy/sigmoidoscopy of remnant colon with polyp removal before teduglutide exposure will be performed in subjects with any colon remnant including 
rectal stump evaluation.  Colonoscopy should be completed during the stabilization period, prior to the baseline visit, if required.  If a subject had a normal 
colonoscopy/sigmoidoscopy within 6 months prior to screening, a baseline colonoscopy/sigmoidoscopy will not be required. 
g At screening, information on all medications taken in the previous 30 days will be collected. 
h This is the first of 2 body weight measurements that will be used to determine drug volume. 
i Interim safety evaluations will be assessed 5 to 7 days after any scheduled visit only if a PN/I.V. change was made.  These measures include 48-hour oral fluid 
intake, 48-hour urine volume, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium. 
j All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily. 
k The optimization assessment should be made by reviewing the 48-hour oral fluid intake and urine output from the Diary and assessing whether the subject 
meets the optimization criteria as described in the protocol. 
 
 
 
 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 50 of 72 
 
Table 6-2 
Schedule of Evaluations and Procedures – Stage 2 
Procedures 
Baseline 
Dosing 
Week 1a 
Dosing 
Week 2 
Dosing 
Week 4 
Dosing 
Week 8 
Dosing 
Week 12 
Dosing 
Week 16 
Dosing 
Week 20 
Dosing 
Week 24 
(or early 
terminationb) 
Visit Number: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Day 
0 
7 
14 
28 
56 
84 
112 
140 
168 
Visit Window (days) 
 
± 2 
± 3 
± 3 
± 5 
± 5 
± 5 
± 7 
± 7 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Crohn’s disease assessmentc 
X 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
 
X 
X 
X 
X 
X 
X 
X 
Evaluation of PN/I.V. 
Xe 
 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Colonoscopy/  
  Sigmoidoscopy 
 
 
 
 
 
 
 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
Body weight and BMI 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X 
 
 
 
 
X 
Safety laboratory tests 
X 
 
X 
X 
X 
X 
X 
X 
X 
Citrulline 
X 
 
 
X 
X 
 
X 
 
X 
Antibodies to teduglutide 
and E. coli protein 
X 
 
 
 
 
X 
 
 
X 
PK sampling 
Xj 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
 
Urine pregnancy test 
X 
 
X 
X 
X 
X 
X 
X 
X 
Drug dispensing 
X 
 
X 
X 
X 
X 
X 
X 
 
Interim safety evaluation 
 
 
[X] g, h 
[X]g 
[X]g 
[X]g 
[X]g 
[X]g 
 
48-hour oral fluid intakei 
(Diary) 
X 
 
X 
X 
X 
X 
X 
X 
X 
48-hour urine outputi 
(Diary) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Teduglutide dosingk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliancel 
 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 51 of 72 
 
Table 6-2 
Schedule of Evaluations and Procedures – Stage 2 
Procedures 
Baseline 
Dosing 
Week 1a 
Dosing 
Week 2 
Dosing 
Week 4 
Dosing 
Week 8 
Dosing 
Week 12 
Dosing 
Week 16 
Dosing 
Week 20 
Dosing 
Week 24 
(or early 
terminationb) 
Visit Number: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Day 
0 
7 
14 
28 
56 
84 
112 
140 
168 
(X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous (volume); V = visit 
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone. 
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance. 
c Subjects with active Crohn’s disease are excluded from the study participation, therefore endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease. 
d A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit. 
e The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.). 
f This is the second of 2 body weight measurements that will be used to determine drug volume. 
g Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium. 
h At the Visit 4/Week 2 interim safety visit, laboratory evaluations and 48-hour I/O are not required.  These will be assessed only if the PN/I.V. adjustment was 
tolerated. 
i All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily. 
j Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7. The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) 
must be specified. 
k Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will then self-inject the study drug at home. 
l Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability. 
 
 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 52 of 72 
 
Table 6-3 
Schedule of Evaluations and Procedures – Stage 3 (Extension) 
Procedures 
First 
Visita (last 
visit for 
Stage 2) 
Mo  
1/13b 
Mo  
2/14 
Mo 
 3/15 b 
Mo  
4/16  
Mo  
5/17 b 
Mo  
6/18 
Mo  
7/19 b 
Mo  
8/20 
Mo  
9/21 b 
Mo 
10/2
2 
Mo 
11/23 b 
Mo 
12 
Final     
(Mo 
24)  
(or 
early 
termi-
nation) 
Visit Number: 
V1 
V2/ 
14 
V3/ 
15 
V4/ 
16 
V5/ 
17 
V6/ 
18 
V7/ 
19 
V8/ 
20 
V9/ 
21 
V10/ 
22 
V11/ 
23 
V12/ 
24 
V13 
V25 
Visit Window (days)  
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
Eligibility, Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examinationc 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight and BMI 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory tests 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG 
X 
 
Xg 
 
 
 
X 
 
 
 
 
 
X 
X 
Colonoscopy/sigmoidoscopy 
of remnant colon 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Citrulline 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
Antibodies to teduglutide 
and E. coli protein 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Drug dispensing 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Interim safety visit 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
[X]d 
Diary e 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
48-hour oral fluid intakef 
(Diary) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
48-hour urine outputf (Diary) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 


Protocol TED-C14-004 
CONFIDENTIAL 
17 Nov 2015 
 
Version 5.0 
Page 53 of 72 
 
Table 6-3 
Schedule of Evaluations and Procedures – Stage 3 (Extension) 
Procedures 
First 
Visita (last 
visit for 
Stage 2) 
Mo  
1/13b 
Mo  
2/14 
Mo 
 3/15 b 
Mo  
4/16  
Mo  
5/17 b 
Mo  
6/18 
Mo  
7/19 b 
Mo  
8/20 
Mo  
9/21 b 
Mo 
10/2
2 
Mo 
11/23 b 
Mo 
12 
Final     
(Mo 
24)  
(or 
early 
termi-
nation) 
Visit Number: 
V1 
V2/ 
14 
V3/ 
15 
V4/ 
16 
V5/ 
17 
V6/ 
18 
V7/ 
19 
V8/ 
20 
V9/ 
21 
V10/ 
22 
V11/ 
23 
V12/ 
24 
V13 
V25 
Visit Window (days)  
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
Evaluation of PN/I.V. (actual 
volume L/week) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Teduglutide dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complianceh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[X]=Possible interim safety evaluation time point (Refer to footnote “d”.); BMI=body mass index; ECG=electrocardiogram; L=liter; Mo=month; 
PN/I.V.=parenteral nutrition/intravenous (support); V=visit 
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the 
Month 1 visit.  Interim (standard of care) visits may be utilized to assess subjects’ well-being (ie, occurrence of adverse events) and to check for any changes in 
medications. 
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed 
appropriate. 
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone. 
c Full physical examination to be performed at first and final visit; a brief examination will be performed at all other study visits. 
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  Hematocrit, 
serum blood urea nitrogen and serum creatinine, and urine sodium will be measured. 
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit. 
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The 
measurements should include 1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily. 
g An ECG will be taken at Visit 3, but not at Visit 15. 
h Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability. 
 
 
 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 54 of 72
7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s CRF by the investigational site 
staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case of 
computerized source data, the investigator has to give the sponsor access to the subject files at 
each monitoring visit. To ensure that data have been entered correctly on the CRF, they will be 
100% source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding any questions or discrepant data. The investigator or designee will be 
responsible for the timely recording of subject data into the CRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The PI or designee will review all CRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will sign the CRF via an electronic signature. The PI
will be responsible for reviewing the data in a timely manner.  Non-CRF data will be sent to the 
sponsor or designee via a data transfer from the appropriate vendor for assimilation into the 
database. Paper copies non-CRF data will be signed and dated by the investigator and filed.
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with CRF guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that should 
be resolved at the study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once the 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 55 of 72
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.
An audit will be performed by the sponsor’s Data Management group. When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the database, 
the database will be ready for statistical analysis by the sponsor or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC.  In the event that the appropriate individual at the site provides an 
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 56 of 72
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.
8
STATISTICAL METHODOLOGY 
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 57 of 72

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the mean percent change in weekly PN/I.V. 
volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the placebo 
group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from Study CL0600-020.  The comparison should take 
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95%
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with 
those from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should 
take into account the anticipated variability of the data due to the small number of subjects 
in Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.
8.2.2
Efficacy and Pharmacodynamics – Stage 3
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 58 of 72
8.3
Safety
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, laboratory safety data, antibodies to teduglutide, and changes in urine 
output, body weight, and BMI.  See Section 6.2 for a full list of safety variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg, number and percentage of subjects) for each treatment group. Adverse 
events will be summarized by severity, relationship to treatment, AEs leading to discontinuation, 
and AEs leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point for each treatment group. 
The number and percentage of subjects classified as having antibodies to teduglutide will be used to 
summarize the presence of antibodies for each treatment group.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study. 
The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow up. The primary population analyzed for 
efficacy will be the ITT population. An additional per-protocol population analysis may also be 
performed as secondary/sensitivity analysis. Applicable analysis populations will be defined in the 
Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 59 of 72
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 60 of 72
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
sponsor has assessed it as an unanticipated problem.  Approval for protocol amendments will be 
transmitted in writing to the investigator. The investigator will provide the IRB with progress 
reports at appropriate intervals (not to exceed one year) and a study summary report following 
the completion, termination, or discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject. A subject information/ICF model will be provided by the 
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 61 of 72
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods.  The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial.  IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 62 of 72
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 63 of 72
10
REFERENCES
None


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 64 of 72
APPENDIX 1:
PN/I.V. OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and 
the health status of the subject will be assessed after 5 to 7 days of the adjustment.  
Laboratory safety samples should be evaluated following a PN/I.V. adjustment (see 
Table A2-3), accompanied by determination of 48-hour I/O and symptoms of dehydration.  
At the interim safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No 
further reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 65 of 72
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 
by targeted urine output of 1.0 to 2.0 L/day.  If a subject has not achieved an optimal 
tolerated volume of PN/I.V. after 8 weeks, consult the sponsor’s Medical Monitor.
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 66 of 72
APPENDIX 2:
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD – STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to 
reduce volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical 
Monitor.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 67 of 72
Table A2-1: PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% (Week 2) or to previous 
level.
1.0 L/day or more and less than 
Baseline
If subject is dehydrated or inadequately nourished (see 
Table A2-2), increase PN/I.V.  If not, maintain PN/I.V.
Baseline or more, and less than a 10% 
increase over Baseline
Maintain PN/I.V.
At least a 10% increase over Baseline
Reduce PN/I.V. by at least 10% of stabilized Baseline level 
up to a clinically appropriate amount (maximum of 30%).
L = liter; PN/I.V. – parenteral nutrition/intravenous (volume)
Table A2-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals 
for hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 
PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be collected to 
evaluate hydration and nutrition (see Table A2-2).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. 
(Reduction of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and 
the health status of the subject will be assessed after 5 to 7 days of the adjustment.  
Laboratory safety samples should be evaluated following a PN/I.V. adjustment (see 
Table A2-3), accompanied by determination of 48-hour I/O and symptoms of dehydration.  


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 68 of 72
At the interim safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No 
further reductions to PN/I.V. volume are made at the interim safety visit.
Table A2-3: Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is dehydrated 
(See Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not 
dehydrated, but is inadequately nourished (See 
Table A2-2)
If possible, maintain PN/I.V. volume and 
increase nutrition. If not, increase PN/I.V. to 
previous volumea
Baseline output or greater and subject is adequately 
hydrated and nourished (See Table A2-2)
Maintain PN/I.V.
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume)
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate 
increase in PN/I.V. is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  During the 
remainder of the study, subjects may undergo 1 additional attempt to reduce volume by 
at least 10%.
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 69 of 72
APPENDIX 3:
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION
TREATMENT PERIOD – STAGE 3)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of OPTIMIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical 
Monitor.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 70 of 72
Table A3-1: PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on 
stabilized urine output
Increase PN/I.V. by at least 10% or to previous level.
1.0 L/day or more and less than Baseline
If subject is dehydrated or inadequately nourished (see 
Table A2-2), increase PN/I.V.  If not, maintain PN/I.V.
Baseline or more, and less than a 10% 
increase over Baseline
Maintain PN/I.V.
At least a 10% increase over Baseline
Reduce PN/I.V. by at least 10% of optimized Baseline level 
up to a clinically appropriate amount (maximum of 30%).
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume)
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily.  All blood and urine samples should be taken at a consistent time period throughout 
the study, convenient for the subject and site staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed after 5 to 7 days of the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. Depending on the 
wellbeing of the subject it is at the discretion of the investigator to abstain from the 
laboratory safety samples.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 71 of 72
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.
Table A3-2: Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
* AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Protocol TED-C14-004
CONFIDENTIAL
17 Nov 2015
Version 5.0
Page 72 of 72
APPENDIX 4:
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study 
in compliance with this protocol, any future amendments, and with any other study conduct procedures 
provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practice 
(GCP) and all other applicable regulatory requirements to obtain written and dated approval from the 
Institutional or Central Review Board (IRB) or Independent Ethics Committee (IRB) for the study 
protocol and any amendments thereof, written informed consent or updates thereof, subject recruitment 
procedures (eg, advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from the sponsor 
and review and documented approval from the IRB, except to eliminate an immediate hazard to the study 
subjects, or when change(s) involves only logistical or administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by 
the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in 
this protocol, and any other information provided by the sponsor or In-country Clinical Caretaker 
including, but not limited to, the current Investigator’s Brochure or equivalent document and approved 
product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the foreseen 
duration of the clinical study in order to conduct the study properly, ethically, and safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)










A 4-Stage Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome
Clinical Study Protocol TED-C14-004
Version 6.0
Phase 3
Sponsor:  
NPS Pharmaceuticals, Inc.*
550 Hills Drive, 3rd Floor
Bedminster, NJ  07921
USA
(*NPS was acquired by Shire, Inc. on 21 February 2015)
Medical Monitor (Medical Expert of the Sponsor):
, MD PhD
 Global Clinical Development
In-Country Clinical Caretaker: 
EPS Associate Co., Ltd.
2-23 Shimomiyabicho, Shinjuku-ku,
Tokyo 162-0822, Japan
TEL:
FAX:
Protocol v1.0:05 August 2014
Protocol v2.0, Amendment 1:20 August 2014 (administrative amendment)
Protocol v3.0, Amendment 1 (corrected):15 September 2014
Protocol v4.0, Amendment 2:03 March 2015
Protocol v5.0, Amendment 3:17 November 2015
Protocol v6.0, Amendment 4:03 April 2017
The information contained in this document is the property of the sponsor. It is understood that the 
information will not be disclosed to others aside from the investigator(s) and duly designated staff, 
applicable IRB(s) and regulatory authorities without prior written approval from the sponsor, except to 
the extent necessary to obtain informed consent from those persons to whom the study drug may be 
administered.


Shire
CONFIDENTIAL
Page 2
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must mail the sponsor’s 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by
the Protocol Form within 24 hours to the sponsor’s Global Drug Safety Department. 
Applicable e-mail address can be found on the form (sent under separate cover) and below. A 
copy of this form must also be sent to the sponsor’s Medical Monitor by e-mail using the 
details below.
Shire Global Drug Safety
E-mail: 
 MD PhD, Medical Monitor
Office:
Mobile:
E-mail:


Shire
CONFIDENTIAL
Page 3
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
SUMMARY
Protocol TED-C14-004
Title of Study: A 4-Stage, Open-label, Multicenter Study Including Long-term Extension to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in Japanese Subjects with 
PN-dependent Short Bowel Syndrome
Protocol No: TED-C14-004
Phase of development:  3
Objectives:  The objectives of this clinical study are to evaluate the safety, efficacy and 
pharmacokinetics (PK) of teduglutide in Japanese subjects with parenteral nutrition 
(PN)-dependent short bowel syndrome (SBS) over a 24-week period followed by a long-term 
extension to evaluate long-term safety and efficacy.
Methodology:  This will be an open-label, multicenter, 4-stage study.  All subjects will 
receive teduglutide 0.05 mg/kg/day.  Stage 1 will include a screening visit; a maximum 
8-week parenteral nutrition/intravenous fluids (PN/I.V.) support optimization period (if 
required); and a stabilization period in which stable administration of PN/I.V. support, defined 
as a targeted urine output of 1.0 to 2.0 L/day while the subject is kept adequately hydrated and 
nourished, is demonstrated for a minimum of 4 weeks up to a maximum of 8 weeks. If a 
subject fails to remain stable for at least 4 consecutive weeks, the subject may start the 
optimization period again, beginning with Visit 1.1. Those subjects who fail to stabilize after 
2 attempts will not proceed further and will not be dosed. Stage 2 will be a dosing period of 
24 weeks, during which subjects will self-administer the study drug at home.
Stages 3 and 4 constitute the long-term extension portion of the study.  In Stage 3, which will 
begin immediately following Stage 2, subjects will continue to receive treatment with
teduglutide 0.05 mg/kg/day for up to 24 months. In Stage 4, which will begin immediately 
following Stage 3, subjects will continue treatment with teduglutide 0.05 mg/kg/day in Study 
TED-C14-004 until teduglutide is commercially available for each subject, the subject’s 
participation in this study is discontinued, or the study is discontinued. 
Any subject who achieves complete independence from PN/I.V. support at any time during 
the Stages 2, 3 or 4 treatment periods will continue to receive teduglutide treatment.  If a 
subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.
Number of subjects planned:  At least 5 subjects may be enrolled.
Diagnosis and main criteria for inclusion:  Men and women outpatients, aged 16 years and 
older at the time of signing the Informed Consent Form (ICF) who meet the following criteria:

Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of the ICF

In clinical remission from Crohn’s disease for at least 12 weeks prior to dosing


Shire
CONFIDENTIAL
Page 4
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

PN/I.V.  support required at least 3 times per week during the week prior to screening and 
during the 2 weeks prior to baseline to meet their caloric, fluid or electrolyte needs

Stable PN/I.V. support for at least 4 consecutive weeks immediately prior to the start of 
treatment with teduglutide, based upon the opinion of the investigator and approval by the 
Sponsor’s Medical Monitor; stability is defined as:

Actual PN/I.V. usage matches prescribed PN/I.V.

Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ± 25% of the respective 48-hour I/O volumes at the time the subject is 
optimized and enters stabilization.

Urine output volume should NOT fall below 2 L and not exceed 4 L per 48 hours 
when the subject completes the optimization and stabilization periods.

Adequate hepatic function at the time of stabilization: 

Total bilirubin < 2 times upper limit of normal (ULN)

Aspartate aminotransferase (AST) < 5 times ULN

Alanine aminotransferase (ALT) < 5 times ULN

Adequate renal function at the time of stabilization:

Serum creatinine < 2 times ULN

Creatinine clearance ≥50 mL/minute (only in subjects with a known history of 
creatinine clearance < 50 mL/min)

Adequate pancreatic function at the time of stabilization:

Serum amylase < 2 times ULN

Serum lipase < 2 times ULN

No unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities 

No radiographic or manometric evidence of pseudo-obstruction or severe known 
dysmotility syndrome

No evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening

No current diagnosis of cancer or history of any cancer except basal cell carcinoma within 
5 years

No evidence of untreated intestinal obstruction or clinically significant active stenosis
Test product, dose and mode of administration:  Teduglutide for subcutaneous (SC) injection 
is provided as a lyophilized powder that must be reconstituted using 0.5 mL sterile water for 
injection and used within 5 minutes of reconstitution.
A daily dose of teduglutide 0.05 mg/kg will be used in this study. The dose calculation will 
be based on an average of the 2 measurements of body weight at the stabilization and baseline 
visits. This calculated dose will be used for the duration of the study, however, it may be 
adjusted for change in a subject’s weight when entering Stage 4 (Visit 26).


Shire
CONFIDENTIAL
Page 5
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Teduglutide will be administered by SC injection once daily into 1 of the 4 quadrants of the 
abdomen (in subjects without a stoma) or either thigh or arm. For subjects with a stoma, the 
quadrant of the abdomen containing the stoma should not be used. The first SC injection 
should be administered under the supervision of the investigator or designee.
Reference therapy, dose and mode of administration:  This is an open-label study.
Duration of treatment:  
In Stage 1, subjects will undergo screening (taking up to 7 days), a maximum 8-week PN/I.V. 
support optimization period (if required), and a stabilization period that demonstrates stable 
administration of PN/I.V. support for a minimum of 4 weeks up to a maximum of 8 weeks
(total maximum 16 weeks for optimization/stabilization periods).  Subjects who fail 
optimization or stabilization may return to the beginning of the optimization period once 
(taking up to an additional 16 weeks).  Therefore the total possible duration of Stage 1 is up to 
33 weeks.
Following Stage 1, subjects will self-administer study treatment at home for 24 weeks in the 
main treatment period (Stage 2).
After the initial 24-week treatment period (Stage 2), subjects will continue teduglutide 
treatment in the initial extension treatment period for up to an additional 24 months (Stage 3).
The extension treatment period will continue in Stage 4 where subjects will receive treatment 
with teduglutide in Study TED-C14-004 until teduglutide is commercially available for each 
subject, the subject’s participation in this study is discontinued, or the study is discontinued.
Criteria for Evaluation
Efficacy and pharmacodynamics – Stage 2:  The efficacy variables are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the 
subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) 
in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
Efficacy and Pharmacodynamics – Stages 3 and 4:  Absolute and percent change from 
baseline in weekly PN/I.V. volume and changes in days per week of PN/I.V. support and 
plasma citrulline levels will continue to be evaluated throughout the long-term extension.
Pharmacokinetics – Stage 2 only:  Single-dose PK will be evaluated on the first day of 
teduglutide treatment (Baseline/Day 0). Samples for PK analysis will be collected and 
recorded pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours 
post-dose.


Shire
CONFIDENTIAL
Page 6
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (V/F)
Safety:  Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory 
safety data, antibodies to teduglutide and to Escherichia coli protein (ECP), and changes in 
48-hour urine output, body weight and body mass index (BMI) will be evaluated.  An 
abdominal ultrasound and colonoscopy/sigmoidoscopy of remnant colon will be done during 
the stabilization period if these procedures were not done in the 6 months prior to screening.  
Colonoscopy/sigmoidoscopy will be repeated at the end of the main treatment period 
(Stage 2) and at the end of the extension treatment period (at Stages 3 and 4).  For all subjects 
with a history of Crohn’s disease, an upper gastrointestinal (GI) contrast series with small 
bowel follow-through will be performed during the stabilization period, prior to the baseline 
visit.
Statistical methods:  No formal testing will be conducted for efficacy or pharmacodynamic 
variables.  For continuous variables, descriptive statistics will be used to summarize median, 
maximum, minimum, mean (± standard deviation [SD]), geometric mean (± standard error
[SE]) and its 95% confidence interval.  For categorical variables, n (%) will be summarized.  
Individual data will be listed.
PK parameter estimates will be calculated using a non-compartmental analysis.
Interim Analysis:  An interim analysis of study data will be done at the completion of the 
24-week Stage 2 study period and again after subjects complete 6 months of treatment in the
Stage 3 extension period (1 year of teduglutide exposure).  A final analysis of study data will 
be done at the end of the study.




Shire
CONFIDENTIAL
Page 8
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
TABLE OF CONTENTS
EMERGENCY CONTACT INFORMATION................................................................................2
SUMMARY.....................................................................................................................................3
SIGNATURE PAGE .......................................................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
INTRODUCTION ..................................................................................................................14
1
1.1
Background ..............................................................................................................14
1.2
Rationale for the Clinical Study...............................................................................16
1.3
Rationale for Study Design ......................................................................................16
OBJECTIVES.........................................................................................................................17
2
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2..............................................17
2.2
Efficacy and Pharmacodynamic Endpoints – Stages 3 and 4 ..................................17
2.3
Pharmacokinetic Endpoints – Stage 2 Only.............................................................17
2.4
Safety Objectives......................................................................................................18
STUDY DESIGN ...................................................................................................................18
3
3.1
Main Treatment Period (Stages 1 and 2)..................................................................18
3.2
Extension Treatment Period (Stages 3 and 4) ..........................................................19
SUBJECT SELECTION AND PARTICIPATION................................................................21
4
4.1
Number of Subjects..................................................................................................21
4.2
Inclusion Criteria......................................................................................................21
4.2.1
Inclusion in Stage 3................................................................................................22
4.3
Exclusion Criteria.....................................................................................................22
4.4
Subject Withdrawal Criteria.....................................................................................25
4.4.1
Events Necessitating Withdrawal from Study .......................................................25
4.4.2
Re-screening of Subjects........................................................................................26
TREATMENTS AND TREATMENT PLAN........................................................................26
5
5.1
Treatments Administered .........................................................................................26
5.1.1
Identification of Investigational Product ...............................................................27
5.1.2
Packaging and Labeling.........................................................................................27
5.1.3
Storage, Accountability, and Stability ...................................................................27
5.2
Dose Regimen ..........................................................................................................28
5.2.1
Selection of Doses in Study ...................................................................................28
5.2.2
Selection and Timing of Dose for Each Subject....................................................28


Shire
CONFIDENTIAL
Page 9
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
5.2.3
Subjects Who Achieve PN/I.V. Independence ......................................................29
5.2.4
Compliance with Dosing Regimens.......................................................................29
5.3
Prior and Concomitant Medications.........................................................................29
STUDY EVALUATIONS AND PROCEDURES .................................................................30
6
6.1
Efficacy Evaluations ................................................................................................30
6.2
Safety Evaluations....................................................................................................30
6.2.1
Adverse Events ......................................................................................................31
6.2.1.1
Adverse Event Definition.......................................................................31
6.2.1.2
Procedures for Reporting Adverse Events .............................................32
6.2.2
Serious Adverse Events .........................................................................................33
6.2.2.1
Serious Adverse Event Definition..........................................................33
6.2.2.2
Procedures for Reporting Serious Adverse Events ................................34
6.2.3
Adverse Events of Special Interest ........................................................................36
6.2.4
Pregnancy Reporting..............................................................................................36
6.2.5
Laboratory Evaluations..........................................................................................37
6.2.6
Plasma Citrulline....................................................................................................38
6.2.7
Women of Child Bearing Potential........................................................................38
6.2.8
48-Hour Oral Fluid Intake and Urine Output ........................................................38
6.2.9
Clinical Assessment of Crohn’s Disease Activity .................................................39
6.2.10 Subject Diaries.......................................................................................................39
6.2.11 Changes in PN/I.V. Volume ..................................................................................39
6.2.12 Medical History and Demographics ......................................................................39
6.2.13 Concomitant Medication Assessment....................................................................39
6.2.14 Physical Examinations...........................................................................................40
6.2.15 Vital Signs and Body Weight ................................................................................40
6.2.16 Electrocardiograms ................................................................................................40
6.2.17 Gastrointestinal-specific Testing ...........................................................................40
6.2.17.1
Colonoscopy/Sigmoidoscopy.................................................................41
6.2.17.2
Abdominal Ultrasound and Upper GI Contrast Series with Small 
Bowel Follow-through ...........................................................................41
6.3
Pharmacokinetic Evaluations ...................................................................................41
6.4
Schedule of Evaluations and Procedures .................................................................41
DATA MANAGEMENT .......................................................................................................50
7
7.1
Data Collection.........................................................................................................50
7.2
Record Retention......................................................................................................51
7.3
Quality Control.........................................................................................................51
STATISTICAL METHODOLOGY.......................................................................................52
8
8.1
Demographic and Baseline Variables ......................................................................52


Shire
CONFIDENTIAL
Page 10
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
8.2
Efficacy and Pharmacodynamic Variables ..............................................................52
8.2.1
Efficacy and Pharmacodynamics – Stage 2...........................................................52
8.2.2
Efficacy and Pharmacodynamics – Stages 3 and 4................................................53
8.3
Safety........................................................................................................................53
8.3.1
Statistical Methods for Safety Variables................................................................53
8.4
Pharmacokinetic Variables – Stage 2 Only..............................................................54
8.5
Analysis Populations, Data Sets, and Time Points...................................................54
8.5.1
Analysis Populations..............................................................................................54
8.6
Statistical/Analytical Issues......................................................................................54
8.6.1
Adjustments for Covariates....................................................................................54
8.6.2
Handling of Dropouts or Missing Data..................................................................54
8.6.3
Interim Analyses ....................................................................................................54
8.6.4
Multiple Comparisons/Multiplicity .......................................................................54
8.6.5
Use of an Efficacy Subset of Subjects ...................................................................54
8.6.6
Examination of Subgroups.....................................................................................55
8.7
Determination of Sample Size..................................................................................55
8.8
Changes to Planned Statistical Analyses..................................................................55
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..................................................55
9
9.1
Declaration of Helsinki and Ethical Review ............................................................55
9.2
Subject Information and Consent.............................................................................55
9.3
Subject Data Protection............................................................................................56
9.4
Payment and Compensation .....................................................................................56
9.5
Changes to the Protocol............................................................................................56
9.6
Confidentiality/Publication of the Study..................................................................57
9.7
Study Termination....................................................................................................57
REFERENCES .......................................................................................................................58
10


Shire
CONFIDENTIAL
Page 11
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
LIST OF TABLES
Table 4-1
Excluded Diseases and Illnesses ...................................................................24
Table 6-1
Schedule of Evaluations and Procedures – Stage 1.......................................43
Table 6-2
Schedule of Evaluations and Procedures – Stage 2.......................................45
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)...................47
Table 6-4
Schedule of Evaluations and Procedures – Stage 4 (Extension)...................49
LIST OF FIGURES
Figure 3-1
Study Diagram...............................................................................................20
LIST OF APPENDICES
Appendix 1
PN/I.V. OPTIMIZATION (STAGE 1) ........................................................59
Appendix 2  
PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT  
PERIOD – STAGE 2) ...................................................................................61
Appendix 3
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION 
TREATMENT PERIOD – Stage 3 and stage 4) ...........................................64
Appendix 4
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE........67


Shire
CONFIDENTIAL
Page 12
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase, equivalent to SGPT
ALX-0600
Teduglutide
AST
Aspartate aminotransferase, equivalent to SGOT
ATC
Anatomic Therapeutic Class
AUC
Area under the plasma concentration-time curve
AUC0–inf
Area under the plasma concentration–time curve from zero to infinity
AUC0–t
AUC from zero to the last measurable concentration
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent clearance
Cmax
Maximum plasma concentration
CRF
Case report form
ECG
Electrocardiogram
eCRF
Electronic case report form
ECP
Escherichia coli protein
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GI
Gastrointestinal 
GLP
Glucagon-like peptide
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
I/O
Oral fluid intake and urine output
IRB
Institutional Review Board
ITT
Intent-to-treat
I.V.
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator


Shire
CONFIDENTIAL
Page 13
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
PK
Pharmacokinetics
PN
Parenteral Nutrition: includes fluids and electrolytes, and may include energy and 
micronutrients 
PN/I.V.
Parenteral Nutrition/Intravenous Fluids
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SUSAR
Suspected, unexpected, serious, adverse reaction
t1/2
Terminal-phase half-life
tmax
Time to Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal 
US
United States
V/F
Apparent volume of distribution
WOCBP
Women of childbearing potential


Shire
CONFIDENTIAL
Page 14
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
INTRODUCTION
1
1.1
Background
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide
(GLP)-2 that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and therefore 
maintains a longer elimination half-life of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines.  The European 
Commission granted a centralised marketing authorization valid throughout the European Union 
for teduglutide (Revestive®) on 30 August 2012 and a New Drug Application for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration on 21 December 2012 for the 
treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral 
support.
Nonclinical Studies
Cardiovascular and respiratory safety pharmacology studies with teduglutide were conducted in 
beagle dogs and no treatment-related effects were observed that were attributed to teduglutide. 
No effect of teduglutide was noted on the in vitro hERG channel or canine cardiac Purkinje 
fibers. In addition no central nervous system effects were observed in rodents in which 
teduglutide was administered at doses well above the targeted clinical therapeutic dose.
Pivotal repeat-dose toxicity studies were conducted in mice and monkeys; genotoxicity was 
studied in mice; carcinogenicity was investigated in rats and mice; reproductive and 
developmental toxicity were investigated in rats and rabbits; and toxicity in juvenile animals was 
investigated in minipigs.
The pattern of toxicity after repeated dosing has been consistent among the various species 
studied, with the majority of the findings observed being associated with the pharmacological 
activity of the drug or with an exaggerated or extended pharmacological effect. In studies 
ranging from 14 days to 26 weeks in mice, up to 104 weeks in rats and up to 1 year in monkeys, 
the primary findings have been an increase in intestinal weight and length, associated with 
structural changes in the intestinal mucosa. A hyperplastic and/or hypertrophic response has 
been reported in the intestines (the target organ for the pharmacological activity of the drug). 
Hyperplasia/hypertrophy was also found in organs that are most likely affected by retrograde 
diffusion (ie, intrahepatic and extrahepatic bile ducts in mouse, rat and monkey, gallbladder in 
mouse and monkey, stomach in monkey, and pancreatic ducts in monkey). The intestinal 
changes in the toxicity studies occurred in a non-dose-related manner (indicating that the plateau 
phase of the dose-response curve had been reached) and were reported at all teduglutide doses. 
For the non-target organs, the findings are considered to represent an extension or exaggeration 


Shire
CONFIDENTIAL
Page 15
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
of the pharmacology of the drug. The intestinal changes largely resolved during a recovery 
period of several weeks.
The effects in the other organs either partially or completely resolved during the recovery period. 
Inflammation at the site of injection was noted in most species, but was most pronounced in 
monkeys.
Teduglutide was negative in standard in vitro and in vivo genotoxicity studies. In a 2-year rat 
carcinogenicity study, an increase in benign tumors in the bile duct and jejunum was observed 
with a clearly defined No-Observed-Effect-Level. These tumors were consistent with the drug’s
activity as a growth factor for the intestine. No treatment- related malignant tumors were 
observed following treatment with teduglutide.
The carcinogenic potential of teduglutide was assessed in two 2-year carcinogenicity studies in 
which teduglutide was administered subcutaneously (SC) in rats and mice.  In Wistar Han rats at 
SC doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in 
the incidences of adenomas in the bile duct and jejunum of male rats.  In Crl:CD1(ICR) mice at 
SC doses of 1, 3.5 and 12.5 mg/kg/day (about 20, 70 and 250 times the recommended daily 
human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary 
adenomas in the gallbladder; it also caused  adenocarcinomas in the jejunum in male mice at the 
highest dose.
Even at high doses, teduglutide did not affect reproductive performance, early embryonic 
development or sperm parameters in rats, did not increase malformations or produce 
developmental toxicity in rats and rabbits, and did not affect pre- and postnatal development in 
rats. The same pharmacological responses were observed in a 90-day juvenile toxicity study in 
minipigs at all doses as were observed in adult mice, rats and monkeys. There were no new or 
unique toxicities that suggested a specific risk in the pediatric population.
Teduglutide is considered non-immunogenic in mice, rats and rabbits, while it induces a weak 
humoral immune response in monkeys. Occurrence of anti-teduglutide antibodies in monkeys 
was neither associated with a reduction in its pharmacological activity in the intestine, nor was it 
consistently associated with a decline in the systemic exposure to teduglutide.
Toxicokinetic analyses revealed that teduglutide was rapidly absorbed following SC injection. 
Maximum concentration (Cmax) and area under the curve (AUC) values generally increased in a 
dose proportional manner with no evidence of accumulation. Male mice and rats tended to 
exhibit higher exposures than females, but this effect was not pronounced and was not observed 
in minipigs or monkeys.
Clinical Studies
Results of the pivotal study filed for the United States (US) New Drug Application, CL0600-020, 
showed that teduglutide at a dose of 0.05 mg/kg/day for up to 24 weeks was superior to placebo 
in reducing parenteral nutrition/intravenous fluids (PN/I.V.) volume in adult subjects with SBS.  


Shire
CONFIDENTIAL
Page 16
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
In this study the responder rate was 62.8% in the teduglutide 0.05 mg/kg/day group with subjects 
achieving a mean reduction from baseline in PN/I.V. volume of 4.4 L/week at Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/I.V. volume reduction, gaining additional days off per week, and achieving complete 
weaning of parenteral support.  The most significant reductions were for those subjects who 
received 24 weeks of teduglutide 0.05 mg/kg/day in Study CL0600-020 and continued treatment 
in Study CL0600-021 for another 24 months.  In this cohort, 10 subjects completely weaned off 
of PN/I.V. support and 18/30 (60.0%) had a reduction in their PN/I.V. requirement of at least 
3 days. It is encouraging that further efficacy was also observed for subjects who initiated 
treatment in Study CL0600-021 (ie, those who received placebo in Study CL0600-020).  After 
only 6 months of treatment, 37.1%  these subjects had at least a 20% reduction in weekly 
PN/I.V. volume, which increased to 55.2% by Month 24.  Two subjects completely weaned off 
of their PN/I.V. support.
Overall, reductions ranged from 13 PN-dependent subjects achieving complete weaning to 25/65 
(38.5%) subjects who demonstrated a reduction of ≥ 3 days/week in their parenteral support by 
the end of study at Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who 
responded in the previous study maintained their response after an additional 24 months of 
teduglutide treatment, demonstrating durability of effect.
The results of this study continue to support the efficacy of long-term treatment with teduglutide 
in PN/I.V.-dependent SBS subjects.
1.2
Rationale for the Clinical Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the European Union (EU) and the US.  The clinical profile and issues 
related to SBS and PN/I.V. in Japan are similar to those in the EU and US.  Therefore, there is an 
unmet medical need for Japanese patients with PN-dependent SBS.  This study is designed to 
provide evidence of safety and efficacy of teduglutide in a Japanese SBS patient population.
1.3
Rationale for Study Design
The design of this study is based on the previously conducted multicenter, multinational pivotal 
study.   The dose, treatment duration and design of the current study are supported by the results 
of previous studies.  Pivotal study CL0600-020 showed that teduglutide at a dosage of 
0.05 mg/kg/day for up to 24 weeks was superior to placebo in reducing PN/I.V. volume in adult 
subjects with SBS.  In the follow-up long-term extension study CL0600-021, there continued to 
be evidence of increased efficacy of teduglutide over time in all groups exposed to teduglutide in 
terms of PN/I.V. volume reduction, gaining additional days off per week, and achieving 
complete weaning of parenteral support.  Among the subjects who received 24 weeks of 
teduglutide treatment in Study CL0600-020 and who continued treatment in Study CL0600-021 
for another 24 months, 10 subjects completely weaned off of PN/I.V. support and 18/30 (60.0%) 
had a reduction in their PN/I.V. requirement of at least 3 days.  Overall, reductions ranged from 
13 PN-dependent subjects achieving complete weaning to 25/65 (38.5%) subjects who 


Shire
CONFIDENTIAL
Page 17
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
demonstrated a reduction of ≥ 3 days/week in their parenteral support by the end of study at 
Month 24.  In addition, 21/22 (95.5%) of teduglutide-treated subjects who responded in the 
previous study maintained their response after an additional 24 months of teduglutide treatment, 
demonstrating durability of effect.
OBJECTIVES
2
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics
(PK) of teduglutide in Japanese subjects with PN-dependent SBS over a 24-week period 
followed by a long-term extension to evaluate long-term safety and efficacy.
2.1
Efficacy and Pharmacodynamic Endpoints – Stage 2
The efficacy endpoints are as follows:

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and at end of treatment [EOT]).  Weekly PN/I.V. volume will be based on the subject 
diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.  A 
response is defined as the achievement of at least a 20% reduction from baseline (Visit 2) in 
weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
2.2
Efficacy and Pharmacodynamic Endpoints – Stages 3 and 4
For Stages 3 and 4, absolute and percent change from baseline in weekly PN/I.V. volume and 
changes in days per week of PN/I.V. support and plasma citrulline levels will continue to be 
evaluated throughout the long-term extension.
2.3
Pharmacokinetic Endpoints – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Baseline/Day 0). 
Samples for PK analysis will be collected and recorded pre-dose, at 15, 30 and 60 minutes 
post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  
The following parameters will be derived:

Area under the plasma concentration–time curve (AUC) from zero to infinity (AUC0–inf)

AUC from zero to the last measurable concentration (AUC0–t)

Maximum plasma concentration (Cmax)

Time to Cmax (tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)


Shire
CONFIDENTIAL
Page 18
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

Apparent volume of distribution (V/F)
2.4
Safety Objectives
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; antibodies to 
teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine output, body 
weight and body mass index (BMI).  An abdominal ultrasound and colonoscopy/sigmoidoscopy 
of remnant colon will be done during the stabilization period if these procedures were not 
performed during the 6 months prior to screening.  Colonoscopy/sigmoidoscopy will be repeated 
at the end of the main treatment period (Stage 2) and at the end of the extension treatment period 
(at Stages 3 and 4).  For all subjects with a history of Crohn’s disease, an upper GI contrast series 
with small bowel follow-through will be performed during the stabilization period, prior to the 
baseline visit.
STUDY DESIGN
3
This will be an open-label, multicenter, 4-stage study, consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide
0.05 mg/kg/day (Stage 2), and a long-term extension (Stages 3 and 4).
3.1
Main Treatment Period (Stages 1 and 2)
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. optimization period (if 
required); and a stabilization period that demonstrates stable PN/I.V. support for a minimum of 
4 weeks to a maximum of 8 weeks.
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine output 
within 2 to 4 L, he/she will enter the optimization period, during which the minimally tolerated 
stable PN/I.V. volume will be determined during a period of up to 8 weeks.  If it is not possible 
to keep the subject adequately hydrated and nourished within the target urine output range, the 
minimally tolerated PN/I.V. volume will be documented.
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2).  
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the subject 
may start the optimization period again, beginning with Week 2 (Visit 1.1). Appendix 1 provides 
details of the optimization procedure.  Those subjects who fail to stabilize after 2 attempts will 
not proceed further and will not be included in Stage 2.
Stage 2 will be a 24-week dosing period, during which subjects will self-administer teduglutide 
0.05 mg/kg/day at home.  Stage 2 will begin with baseline assessments of hydration and 
nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 8 weeks.  At least 


Shire
CONFIDENTIAL
Page 19
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
5 subjects will be enrolled.  The on-treatment study visits will occur at Weeks 2, 4, 8, 12, 16 and 
20, with the last scheduled visit at Week 24 of Stage 2.
3.2
Extension Treatment Period (Stages 3 and 4)
Stages 3 and 4 constitute the long-term extension portion of the study. Stage 3, which will begin 
immediately following Stage 2, will include subjects who complete the main treatment period 
and who are willing to continue with treatment teduglutide 0.05 mg/kg/day SC for up to an 
additional 24 months. In Stage 4, which will begin immediately following Stage 3, subjects will 
continue treatment with teduglutide 0.05 mg/kg/day SC in Study TED-C14-004 until teduglutide 
is commercially available for each subject, the subject’s participation in this study is 
discontinued, or the study is discontinued.
Any subject who achieves complete independence from PN/I.V. support at any time during the 
Stages 2, 3 or 4 treatment periods will continue to receive teduglutide treatment.  If a subject 
relapses following achievement of PN/I.V. independence, PN/I.V. support will be re-initiated 
and the subject will continue receiving teduglutide.
A schematic representation of the study design is presented in Figure 3-1.


Shire
CONFIDENTIAL
Page 20
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Figure 3-1
Study Diagram
PN/I.V. 
stabilization
Teduglutide 0.05 mg/kg/day 
(n ≥5)
4 to 8 weeks
24 weeks
0 to 8 weeks
Stage 1
Stage 2
PN/I.V.
optimization
Screening
1 to 7 days
Teduglutide 0.05 mg/kg/day 
(n ≥5)
24 months 
Stage 3
Until drug is commercially available
for each subject, or subject’s 
participation or study are discontinued
Stage 4
Teduglutide 0.05 mg/kg/day 
(n ≥ 5)


Shire
CONFIDENTIAL
Page 21
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Schedules of evaluations for Stage 1, 2, 3 and 4 can be found in Table 6-1, Table 6-2, Table 6-3, 
and Table 6-4, respectively.
Procedures to adjust or reduce PN/I.V. volume during the optimization can be found in
Appendix 1 and during treatment periods in Appendix 2 and Appendix 3, and should be followed 
carefully throughout the study.
SUBJECT SELECTION AND PARTICIPATION
4
4.1
Number of Subjects
At least 5 subjects with PN/I.V.-dependent SBS will be enrolled.
4.2
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study: 
1.
Signed and dated Informed Consent Form (ICF) before any study-related procedures are 
performed
2.
Men and women, 16 years of age or older at the time of signing the ICF 
3.
Subjects with SBS as a result of major intestinal resection (eg, due to injury, volvulus, 
vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of 
PN/I.V. dependency prior to signature of ICF
4.
For subjects with a history of Crohn’s disease, the subject should be in clinical remission for 
at least 12 weeks prior to dosing as demonstrated by clinical assessment, which may include 
procedure-based evidence of remission.
5.
PN/I.V. requirement of at least 3 times per week during the week before screening and 
during the 2 weeks prior to baseline to meet caloric, fluid or electrolyte needs
6.
Stable PN/I.V. requirement for at least 4 consecutive weeks immediately prior to the start of 
teduglutide treatment, based upon the opinion of the investigator and approval by the 
sponsor’s Medical Monitor or designee; stability is defined as:
a.
Actual PN/I.V. usage matches prescribed PN/I.V.
b. Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall within 
± 25% of the respective 48-hour I/O volumes at the time subject is optimized and 
enters stabilization
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours when the subject completes the optimization and stabilization periods.


Shire
CONFIDENTIAL
Page 22
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
4.2.1
Inclusion in Stage 3
Subjects who meet the following criterion will be enrolled in Stage 3 and Stage 4 of this study:
1.
Completion of 24 weeks of dosing and still meeting the criteria for enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded:
1.
Participation in a clinical study using an experimental drug within 30 days or an 
experimental antibody treatment within 3 months prior to signing the ICF, or concurrent 
participation in any clinical study using an experimental drug that would affect the safety of 
teduglutide
2.
Previous use of native GLP-2 or human growth hormone within 6 months prior to screening
3.
Previous use of intravenous glutamine, octreotide, GLP-1 analog, or dipeptidyl peptidase-IV 
inhibitors within 30 days prior to screening
4.
Previous use of teduglutide
5.
Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
the past 3 months
6.
Subjects with active Crohn’s disease or subjects who require biological therapy 
(eg, anti-tumor necrosis factor or natalizumab) that had been introduced or changed during 
the 6 months prior to screening
7.
Subjects with inflammatory bowel disease who require chronic systemic immunosuppressant 
therapy that was introduced or changed during the last 3 months
8.
Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA 
abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
9.
Radiographic or manometric evidence of pseudo-obstruction or severe known dysmotility 
syndrome
10. Evidence of clinically significant obstruction on upper GI series with small bowel 
follow-through done within 6 months prior to screening
11. Major GI surgical intervention within 3 months prior to screening (insertion of feeding tube 
or endoscopic procedure is allowed)


Shire
CONFIDENTIAL
Page 23
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
12. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair
13. Currently diagnosed with cancer or a history of any cancer except basal cell carcinoma 
within 5 years
14. Active clinically significant pancreatic or biliary disease
15. More than 4 SBS-related or PN-related hospital admissions (eg, catheter sepsis, bowel 
obstruction, severe water-electrolyte disturbances) within 12 months prior to screening visit
16. Hospital admission, other than scheduled, within 30 days prior to screening
17. Signs of severe hepatic impairment at time of stabilization:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN); for subjects with 
Gilbert’s disease, direct (conjugated) bilirubin level ≥2 times ULN
b. Aspartate aminotransferase (AST) ≥5 times ULN
c.
Alanine aminotransferase (ALT) ≥5 times ULN
18. Signs of disturbed renal function at time of stabilization:
a.
Serum creatinine ≥2 times ULN
b. Creatinine clearance < 50 mL/minute*
*Only applies to subjects with a known history of creatinine clearance (CrCl) 
< 50 mL/min who then will be required to have a CrCl ≥ 50 mL in order to participate 
in the study.  If a CrCl cannot be measured, an estimated glomerular filtration rate 
(eGFR) may be calculated.
19. Clinical signs of abnormal pancreatic condition, with abnormal laboratory results at time of 
stabilization including:
a.
Serum amylase level ≥2 times ULN
b. Serum lipase level ≥2 times ULN
20. Pregnant or lactating women
21. Female subjects who are not surgically sterile or postmenopausal (defined as 55 years or 
older and/or at least 2 years had elapsed since her last menses) or who are not using 
medically acceptable methods of birth control during and for 30 days after the treatment 
period
22. Not capable of understanding or not willing to adhere to the study visit schedule and other 
protocol requirements


Shire
CONFIDENTIAL
Page 24
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
23. Evidence of untreated intestinal obstruction or clinically significant active stenosis
24. Any condition or circumstance that in the investigator’s opinion put the subject at any undue 
risk, prevented completion of the study, or interfered with analysis of the study results
25. Presence of any of the excluded disease states described in Table 4-1
Table 4-1
Excluded Diseases and Illnesses
Body system or disease 
type
Known conditions excluded
Related to SBS
Ongoing radiation enteritis or the presence of damaged enteral tissue due to 
radiation enteritis
Active celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal
Active inflammatory bowel disease that requires chronic systemic 
immunosuppressant therapy that was introduced or changed during the last 
3 months
Crohn’s disease or other diseases that require biological therapy (eg, anti-
tumor necrosis factor or natalizumab) that was introduced or changed in the 
last 6 months
Untreated known pre-malignant or malignant change in upper or lower GI 
biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial adenomatous polyposis, 
Peutz-Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, 
Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Gardner’s syndrome, 
Cronkhite-Canada syndrome)
Intestinal or other major surgery scheduled within the time frame of the study
Chronic active pancreatitis or active cholecystitis
Immune
Compromised immune system (eg, acquired immune deficiency syndrome, 
severe combined immunodeficiency), hypersensitivity or allergies to 
teduglutide or its constituents or GLP-2
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness


Shire
CONFIDENTIAL
Page 25
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 4-1
Excluded Diseases and Illnesses
Body system or disease 
type
Known conditions excluded
General
Significant active, uncontrolled, untreated systemic diseases (eg, 
cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or central 
nervous system)
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to further treatment.  Discontinued subjects will not 
be replaced.
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
subject’s medical records.  If the reason is not disclosed, every effort must be made up to 
establish whether the reason was an AE and, if so, this must be reported in accordance with the 
procedures described in Section 6.2.1.2.  As far as possible, all examinations scheduled for the 
early termination evaluations must be performed on all subjects who participate, but do not 
complete the study according to the protocol.
4.4.1
Events Necessitating Withdrawal from Study 
The sponsor or designee should be consulted prior to premature withdrawal of a subject. The 
occurrence of any of the following events may necessitate premature withdrawal of a subject 
from the study:

Development of any of the following Inclusion/Exclusion criteria that would interfere with 
analysis of the study results (ie, compromise PN/I.V.):

Significant active, uncontrolled diseases (eg, cardiovascular, renal, cancer) that would 
put the subject at any undue risk or prevent completion of the study

Major surgical interventions (eg, abdominal, vascular)

Crohn’s disease flare up

Use of any excluded medication

Pregnant and lactating women

Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Investigator/Sponsor decision (ie, subject non-compliance with study procedures)


Shire
CONFIDENTIAL
Page 26
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
4.4.2
Re-screening of Subjects
In the event that a subject withdraws from the study in Stage 1, that subject may be re-screened 
upon the approval of the sponsor. A new subject number will be assigned.
Subjects whose urine output cannot be stabilized during the stabilization period after 1 repeated 
effort may not be rescreened.
TREATMENTS AND TREATMENT PLAN
5
After signing the ICF, the subject will enter Stage 1 of the study, which includes screening, 
optimization and stabilization. The purpose of this stage is to ensure that all subjects are 
receiving and tolerating a stable minimal (optimized) level of PN/I.V. volume before treatment 
with teduglutide. If needed, the subject will enter an 8-week maximum optimization period, 
during which the PN/I.V. volume will be adjusted stepwise in targeted increments of 10% or 
more of the previous visit’s volume (Appendix 1). Once the PN/I.V. volume is optimized, the 
subject will enter a minimum 4-week to 8-week stabilization period.
The aim of the study is to evaluate the efficacy of teduglutide in allowing reductions of PN/I.V.
volume to less than the stabilized PN/I.V. level. After completion of the PN/I.V. stabilization 
period, subjects will enter Stage 2 of the study and receive teduglutide for a 24-week dosing 
period. The algorithm for the stepwise reduction of PN/I.V. during the Stage 2 dosing period is 
in Appendix 2.
Stages 3 and 4 constitute the long-term extension portion of the study. Stage 3 will begin 
immediately following Stage 2 and Stage 4 immediately following Stage 3.  In Stages 3 and 4, 
subjects can continue teduglutide treatment if deemed appropriate by the investigator.  During 
the extension, the PN/I.V. dosage will be adjusted as described in Appendix 3.  Subjects will 
continue to receive teduglutide 0.05 mg/kg/day in Stage 3 for up to 24 months then in Stage 4 
until teduglutide is commercially available for each subject, the subject’s participation in this 
study is discontinued, or the study is discontinued.  
Any subject who achieves complete independence from PN/I.V. support at any time during 
Stages 2, 3 or 4 will continue to receive teduglutide treatment.  If a subject relapses following 
achievement of PN/I.V. independence, PN/I.V. support will be re-initiated and the subject will 
continue receiving teduglutide.
5.1
Treatments Administered
Teduglutide 0.05 mg/kg/day will be administered daily at home by the subjects, who will 
self-administer the study drug by SC injection into either thigh or arm or one of the 4 quadrants 
of the abdomen (in subjects without a stoma).  For subjects with a stoma, the quadrant of the
abdomen containing the stoma should not be used.


Shire
CONFIDENTIAL
Page 27
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
5.1.1
Identification of Investigational Product
Teduglutide for SC injection is provided as a lyophilized powder that must be reconstituted using 
0.5 mL sterile water for injection, and used within 5 minutes of reconstitution. The Injection 
Instruction Leaflets will be provided separately.  Each 3.0 mL vial contains 5 mg of teduglutide.
Active ingredient:teduglutide
Added ingredients:L-histidine, mannitol, monobasic and dibasic sodium phosphate
Route of administration:SC injection
Dose:0.05 mg/kg/day
5.1.2
Packaging and Labeling
Study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee. The study drug kit labeling will include the protocol number, the investigational drug 
warning, storage conditions, expiry date, drug name or drug code, lot number, sponsor name and 
country and In-Country Clinical Caretaker name and address. All medication supplied to be 
used in this study will be manufactured, tested, labeled, and released according to current legal 
requirements and Good Manufacturing Practice.  Ancillary supply kits containing the following 
will also be provided with the study drug at each visit:

Pre-filled syringes of sterile water for injection

Needles to affix to sterile water for injection syringes for reconstitution; or vial adaptors for 
reconstitution and withdrawal of the reconstituted study drug into the dosing syringe

Syringes and needles for injection (dosing)

Alcohol swabs
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the center until the sponsor or designee has received all 
required documents from the study center in accordance with applicable regulatory requirements 
and relevant standard operating procedures.
The investigator or designee will conduct an inventory upon receipt of the clinical supplies and 
will acknowledge receipt of the supplies to the sponsor or designee. A copy of the shipping 
documents must be maintained for the investigator’s records. Study drug must be kept in a 
locked area with access restricted to specific study personnel.  Study drug must be stored 
refrigerated at a temperature between 2 and 8oC (36 to 46oF) until dispensed.  Once dispensed to 
a subject, the study drug and the sterile water diluent should be kept at 15 to 25o C (59 to 77oF).
If there are concerns that this temperature cannot be maintained, the study drug may be 
refrigerated.  Therefore, the overall acceptable storage temperature range is 2 to 25oC (36 to 
77oF).


Shire
CONFIDENTIAL
Page 28
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Study drug kits will be dispensed to subjects at each of the study visits. Each study drug kit is 
sufficient for a treatment period of 1 week and enough kits are to be supplied to cover the period 
until the next planned study visit.  The number of study kits dispensed at a study visit may be 
adjusted and study kits may be dispensed between study visits as an option at the discretion of
the investigator and the subject.  Additional study kits will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies. This record will be made available to the sponsor’s monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded, with an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
All used and unused study drug vials, including the supplies must be returned by the subjects and 
retained at the center until instructions are received for return and/or destruction of supplies. 
Further details will be provided in the study reference manual.
5.2
Dose Regimen
The volume of reconstituted study drug is to be administered at a fixed dose of 0.05 mg/kg. The 
dose will be calculated as an average of the 2 measurements of body weight at the stabilization 
and baseline visits. The dose of study drug administered at baseline should be maintained 
throughout the study period without adjustments for changes in a subject’s weight except at 
Visit 26 when entering Stage 4 of the study.
5.2.1
Selection of Doses in Study
The dose of teduglutide selected for this study is based on the efficacy and safety results of up to 
2 ½ years of treatment in prior studies, as discussed in Section 1.3.  Due to the favorable 
risk/benefit profile, the teduglutide dose of 0.05 mg/kg/day was chosen as the dose for all adult 
safety and efficacy studies.
5.2.2
Selection and Timing of Dose for Each Subject
The study drug (teduglutide 0.05 mg/kg/day) will be self-administered immediately after 
reconstitution by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm. Subjects will be trained to self-inject teduglutide on Day 0.  The first SC injection should 
be administered under the supervision of the investigator or designee and the subject observed 
for at least 4 hours. Detailed instructions for reconstitution and injection of the study drug can be 
found in the Injection Instruction Leaflets and the study reference manual. Each day, the 
injection site should be changed. Subjects with a stoma must avoid using the abdominal 
quadrant in which the stoma is situated. 
The subject should be dosed at approximately the same time each day. If a subject forgets to 
take drug, that day’s dose should be administered as soon as possible, even if this is later in the 
day or evening. Consecutive doses should be separated by approximately 12 hours.
First dosing with investigational product must be performed after the blood drawn for antibody 
testing at baseline (Visit 2) in Stage 2. Once the subject has started teduglutide treatment, dosing 


Shire
CONFIDENTIAL
Page 29
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
must be performed at least 14 hours prior to the blood drawn for antibody testing, which will be 
performed at: Baseline and Weeks 12 and 24 during Stage 2; Months 6, 12, 18, and 24 (or early 
termination) during Stage 3; and every other visit (every 6 months) and end-of-study (or early 
termination) visit during Stage 4.
The investigator is responsible for contacting the sponsor or designee prior to interrupting or 
modifying the subject’s daily study drug dosing regimen, ie, as consideration for tolerability 
issues.
A single discontinuation period of study drug should not exceed 10 consecutive days. Dosage 
interruptions of study drug are permissible for a maximum of 21 days total per each 24-week 
period throughout the study.
Dates of days with missed or incomplete doses are to be reported in the diary.
5.2.3
Subjects Who Achieve PN/I.V. Independence
Any subject who achieves complete independence from PN/I.V. support at any time during the 
Stages 2, 3 or 4 treatment periods will continue to receive teduglutide treatment.  A subject will 
be considered to have achieved independence from PN/I.V. (completely weaned off PN/I.V.) if 
the investigator prescribes no PN/I.V. and there is no use of PN/I.V. recorded in the subject diary 
at the last dosing visit. 
If a subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be 
re-initiated and the subject will continue receiving teduglutide.
5.2.4
Compliance with Dosing Regimens
Subject compliance with study drug dosing will be monitored by the sponsor or designee by 
counting and examining used and unused vials. In addition, compliance will be checked at every 
visit by asking the subjects if they have taken their study drug according to instructions and by 
performing drug accountability.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
5.3
Prior and Concomitant Medications
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/I.V. must be recorded from screening and for the duration of the study in the appropriate 
sections of the CRF. Any diagnostic, surgical or other therapeutic treatments received by a 
subject during the course of the study will also be recorded on the CRF.
No new medications should be started unless medically necessary and prescribed by the 
investigator or by another qualified physician involved in the subject’s clinical care and who is 
aware of the subject’s study participation.  


Shire
CONFIDENTIAL
Page 30
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
The mechanism of action of teduglutide may increase absorption of orally administered drugs 
(eg, motility medication, warfarin, psychotropics, and digoxin), so consideration should be given 
to modifying concomitant medication regimens.  Down-titration of concomitant medication 
dosages should be considered when drugs, including those with a narrow therapeutic range, are 
given, especially if given at dosages that are higher than usual.
STUDY EVALUATIONS AND PROCEDURES
6
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics of 
teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period (Stage 2) 
followed by a long-term extension (Stages 3 and 4) to evaluate safety and continued efficacy.
6.1
Efficacy Evaluations
Reductions in PN/I.V. volume form the basis for most of the efficacy evaluations. The 
procedures for the stepwise reduction of PN/I.V. during Stages 2 to 4 of this study are given in 
Appendix 2 (Stage 2) and Appendix 3 (Stages 3 and 4).
As described in Section 2.1, the efficacy endpoints for Stage 2 are as follows: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24.

Change in days per week of PN/I.V. support

Changes in plasma citrulline levels from baseline to Week 24 (or EOT)
In Stages 3 and 4, absolute and percent change from baseline in weekly PN/I.V. volume and 
changes in days per week of PN/I.V. support and plasma citrulline levels will continue to be 
evaluated throughout the long-term extension (see Section 2.2).
Single-dose pharmacokinetics will be evaluated on the first day of teduglutide treatment (Day 0) 
in Stage 2 only, and pharmacokinetic parameters will be derived as described in Section 2.3.
6.2
Safety Evaluations
Safety will be assessed by evaluations of the following variables:

Adverse events, including GI symptoms

12-lead ECGs

Vital signs, including changes in body weight and BMI

Laboratory safety data, including electrolyte balance

Antibodies to teduglutide and ECP (see Table 6-1, Table 6-2, Table 6-3, and Table 6-4 for 
timing)

Changes in urine output (48-hour oral fluid intake/urine output)


Shire
CONFIDENTIAL
Page 31
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

Abdominal ultrasound

Upper GI contrast series with small bowel follow-through

Colonoscopy/sigmoidoscopy of remnant colon

Physical examinations
6.2.1
Adverse Events
During the study, the investigator is responsible for the detection and documentation of any AE 
or SAE, as defined in this protocol.
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product. An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


Shire
CONFIDENTIAL
Page 32
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
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 6.2.1.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors unless these result in an SAE. The categories 
below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – An accidental or intentional administration of an excessive dose of a product

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
6.2.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  Adverse events will be recorded from the 
signing of the ICF and for the duration of the study.   Adverse events that are not resolved at the 
end of study will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the AE is 
judged by the investigator to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the CRF.  The AE term 
should note the diagnosis whenever possible, not the individual signs or symptoms (eg, 
myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, and 
abnormal ECG).  Also recorded are: 

Start and stop date and time (date the site becomes aware of the SAE)

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)


Shire
CONFIDENTIAL
Page 33
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities

Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities

Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required

Relationship to study drug (not related, related): identify relationship as “related” if a causal 
relationship between the investigational product and an AE is at least a reasonable possibility
(see Section 6.2.2.2 for additional guidance on relationship to study drug)

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2 below.

Actions taken (none; study drug dose changed, interrupted, or discontinued; other medication 
change; nondrug therapy) 

Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with sequelae, 
recovering/resolving, unknown, fatal).  An individual AE receives only one outcome.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator (ie, not part of the subject’s medical 
history),

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
An SAE must be recorded on the SAE Form. An SAE requires expeditious handling to comply 
with regulatory requirements.  Any SAEs occurring from the signing of the ICF through 30 days 
after the last dose of study drug or the end of the study, whichever is longer, will be captured and 
must be reported within 24 hours after the investigator is made aware of the event. 
6.2.2.1
Serious Adverse Event Definition
An SAE is defined as an AE that results in any of the following outcomes:

Death 

Is life-threatening. A life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred. It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect


Shire
CONFIDENTIAL
Page 34
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study 

Elective treatment of a condition unrelated to the studied indication or its treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

Part of the normal treatment or monitoring of the studied indication and not associated with 
any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
All initial and follow-up SAE reports must be reported by the investigator to the sponsor’s
Global Drug Safety Department and the CRO/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 6.2.1.1) unless they result 
in an SAE.
The investigator must complete, sign, and date the sponsor’s Clinical Study Serious Adverse 
Event and Non-serious AEs Required by the Protocol Form and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and e-mail the form to the sponsor’s Global Drug 
Safety Department. A copy of the sponsor’s Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form (and any applicable follow-up reports) must also be 
sent to the sponsor’s Medical Monitor using the details specified in the emergency contact 
information section of the protocol.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but an SAE criterion.  The SAE term is the medical event that led to the hospitalization.  
Surgery is not an AE, but the event that required the subject to have surgery is the SAE term.  
Death is not an SAE, but an outcome.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 


Shire
CONFIDENTIAL
Page 35
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the SAE form.  The 
investigator should make the causality assessment based on the information available at the time 
of the event.  The causality can be updated at a future date if additional information is received.
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 event 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 event, then the event 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.
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol.
As required by ICH guidelines and global health authorities, the sponsor or designee will notify 
investigators of all adverse drug reactions that are serious, unexpected, and deemed by the 
reporting investigator or sponsor to be related to study drug (suspected, unexpected, serious, 
adverse reaction [SUSAR]).  Causality, while assessed, does not negate reporting requirements 
to the sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if it 
is not in the appendix to the Investigator Brochure (IB) that contains the compound adverse drug 
reactions; or if the event is of greater frequency, specificity, or severity than is recorded in the 


Shire
CONFIDENTIAL
Page 36
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
IB.  The investigator will receive a copy of the current valid version of the IB prior to the start of 
the study.  The investigator will not be required to assess expectedness, nor should expectedness 
impact the investigator reporting SAEs within the timeframe herein defined.
The investigator should also comply with the Institutional Review Board (IRB) procedures for 
reporting any other safety information (eg, autopsy reports).  
The sponsor or its designee will be responsible for submitting SUSAR reports to the appropriate 
health authorities.  These reports will be submitted within the expedited timeframe.
6.2.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
For AEs of special interest, the Shire Global Drug Safety Department must be informed within 
24 hours of first awareness as per the SAE notification instructions described in Section 6.2.2.2
even if the event does not fulfill seriousness criterion.
6.2.4
Pregnancy Reporting
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 3.2.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Drug Safety Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol.  
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 


Shire
CONFIDENTIAL
Page 37
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine β-hCG test or 
ultrasound result will determine the pregnancy onset date.
6.2.5
Laboratory Evaluations
Laboratory results can vary depending on whether samples are drawn on an on- or off-PN/I.V. 
day, so it is important that every effort be made to draw laboratory samples on the same type of 
infusion day (ie, on- or off-PN/I.V.) throughout the study.  Although subjects do not need to be 
in a fasted state at the time of their clinic visit, they should avoid large meals or large volumes of 
fluid, including PN/I.V. with lipids, within 3 hours of the clinic visit to permit consistent 
assessment.  If peripheral venous access is not possible, the sample may be drawn from the 
central line.  A home nursing visit may be appropriate to collect samples in some circumstances.  
The site’s clinical laboratory will centrifuge and send the samples to the central lab, SRL 
Medisearch Inc. to be analyzed.  Citrulline, antibody, and PK samples will be handled according 
to procedures specified in the laboratory manual.
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs if they are not related to the subject’s underlying condition or their previous 
comorbid medical history (unless they are a worsening of the condition).  A result outside of the 
normal range may be repeated for confirmation.  Any laboratory test result that meets the criteria 
for an SAE (Section 6.2.2) must also be recorded in an SAE Form so that the sponsor or designee 
can collect additional information about that abnormality, including information regarding 
relationship to investigational product or other causes, any action taken, and outcome.
The following laboratory parameters will be collected according to the Schedule of Evaluations 
and Procedures outlined in Table 6-1, Table 6-2, Table 6-3, and Table 6-4:

Hematology
Hemoglobin, hematocrit, erythrocyte count, platelet count, and leukocyte count with differential 

Serum chemistry
Albumin; alkaline phosphatase; ALT; amylase; AST; total, direct, and indirect bilirubin; blood 
urea nitrogen; calcium; chloride; total-cholesterol; C-reactive protein; creatinine; creatinine 
clearance; gamma glutamyl transferase; glucose; lipase; magnesium; phosphate; potassium; 
sodium; triglycerides; and uric acid

Urinalysis
Blood, glucose, leucocytes, microscopic, pH and osmolality, protein, and sodium  

Pregnancy test
Urine pregnancy test (women of childbearing potential [WOCBP] only)


Shire
CONFIDENTIAL
Page 38
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017

Antibodies to teduglutide and ECP
Blood samples for analyses of antibodies to teduglutide and to ECP will be collected at baseline 
and at Weeks 12 and 24 (or early termination) during Stage 2 of the study; at Months 6, 12, 18, 
and 24 (or early termination) during Stage 3; and at every other visit (every 6 months) and end-
of-study (or early termination) visit during Stage 4. Blood sample for antibody testing is to be 
collected at study site prior to first investigational product administration. Once the subject has 
started teduglutide treatment, samples must be drawn at least 14 hours after dosing.
Antibody testing is a 3-step process. If a sample tests negative, no further testing is done. If a 
sample tests positive, further testing is done for teduglutide-specific antibodies. If 
teduglutide-specific antibodies are detected, the test is deemed “positive” and the titer derived,
and neutralizing antibody testing is done. Subjects who test positive for teduglutide-specific 
antibodies may remain on treatment and blood samples for antibody testing will continue to be 
collected as per protocol schedule.
Blood samples for anti-teduglutide antibody testing may be stored and then analyzed together 
periodically to streamline the testing procedure. However, if an investigator suspects that a 
subject is experiencing an AE that may be associated with the development of anti-drug 
antibodies, relevant samples will be tested for the presence of anti-drug antibodies upon request. 
6.2.6
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedule of Evaluations and Procedures (Table 6-2, Table 6-3, and Table 6-4).  If peripheral 
venous access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the laboratory manual.
6.2.7
Women of Child Bearing Potential
Women of childbearing potential who are younger than 55 years or are not surgically sterile must 
have a negative urine pregnancy test result at screening and baseline to be enrolled. Pregnancy 
tests will also be performed at each on-treatment study visit. Sexually active WOCBP and 
partners of male subjects must use highly effective and medically acceptable methods of birth 
control during and for 30 days after the treatment period (ie, abstinence, oral contraceptive pills 
with barrier methods and spermicide, transdermal or injectable contraceptives, intrauterine 
device, surgical sterilization of partner), in a manner such that the risk of failure is minimized. 
The investigator will discuss which methods the subject will prefer to use.  For a woman to be 
considered postmenopausal, at least 2 years must have elapsed since her last menses.
At the time of signing the ICF, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control during 
and for 30 days after the treatment.
6.2.8
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to each study visit at which this is required (all visits during 


Shire
CONFIDENTIAL
Page 39
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Stages 1 and 2), and at the visits specified in Table 6-3 (Stage 3) and Table 6-4 (Stage 4). The 
center staff will contact the subject at least 48 hours before the scheduled visits to remind the 
subject to start measuring I/O, and to record these measurements into the diary.  At these times 
of 48-hour measurements, oral fluid intake must remain as stable as possible compared with 
baseline.  These measurements will also be collected at all interim safety visits.
6.2.9
Clinical Assessment of Crohn’s Disease Activity
Any subject enrolled in the study with a history of Crohn’s disease will have clinical status 
assessed at screening and again at the baseline visit in Stage 2 to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation; therefore, endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.  In addition, upper GI contrast series with small 
bowel follow-through is required in subjects with a history of Crohn’s disease to detect any
clinically significant active stenosis and/or active stricturing that may need to be addressed.
6.2.10
Subject Diaries
Subjects will be required to record their 48-hour oral/enteral dietary intake, PN/I.V. support 
(volume), drug dosing (as applicable), and urine output on paper diaries throughout the 
screening, optimization and stabilization periods, and the treatment periods in Stages 2 to 4 of 
the study.  Diaries should be distributed initially at the time the subject signs consent. Subjects 
should be instructed to record the 48-hour oral intake/urinary output prior to the screening visit 
(Visit 1.0) in order to assess their eligibility for stabilization.
6.2.11
Changes in PN/I.V. Volume
The PN and I.V. fluid volumes and constituents are prescribed by the physician. The actual PN 
and I.V. fluid administered since the last visit will be recorded daily in a paper diary by the 
subject or designee. Designee may enter data on behalf of the subject if he/she is physically 
unable to enter data on his/her own. If the subject has a TEAE that prevents him or her from 
adhering to study requirements, including PN/I.V. volume adjustments, the subject may be 
withdrawn from the study (Section 4.4.1). 
Physician-directed changes in a subject’s PN/I.V. volume must be followed by an interim safety 
visit 5 to 7 days after the scheduled visit when a reduction has taken place. Subjects should be 
instructed to perform a 48-hour I/O collection during the 48 hours before the interim safety visits 
in Stages 2 to 4 of the study.  At the interim visits the PN/I.V. will be changed if the previous 
adjustment was not tolerated.
6.2.12
Medical History and Demographics 
Information on medical history and demographic data is to be recorded on the appropriate CRF.
6.2.13
Concomitant Medication Assessment
The subject’s usage of concomitant medication will be recorded during screening and assessed at 
each scheduled visit for the duration of the study.  The details of any medications and changes 
therein (change in medication or dosage of medication) will be recorded on the CRF. Any 


Shire
CONFIDENTIAL
Page 40
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
diagnostic, surgical or other therapeutic treatments received by a subject during the course of the 
study will also be recorded on the CRF.
6.2.14
Physical Examinations
Physical examinations will consist of assessments of head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities and respiratory, GI, musculoskeletal, cardiovascular, nervous and dermatologic 
systems.  The physical examination should be performed by the same person each time, 
whenever possible.  A full physical examination is to be performed at screening and at the first 
and last visits of Stage 2 and Stage 3, and at every scheduled visit and end-of-study (or early 
termination) visit of Stage 4.  A brief examination of the GI and cardiovascular systems will be 
made at all other study visits.  Other body systems will be examined as clinically indicated.
6.2.15
Vital Signs and Body Weight
Vital signs will be measured according to the Schedule of Evaluations and Procedures (Table 
6-1, Table 6-2, Table 6-3, and Table 6-4). Vital signs will include systolic and diastolic blood 
pressure (mmHg), pulse (beats/minute), and body temperature (ºC) after the subject has been 
sitting for 5 minutes.  Body weight (kg) and BMI also will be recorded.  Height will be recorded 
at screening and at the initial visits of Stages 2 and 3.  
Any clinically significant changes (in the opinion of the investigator) noted in vital signs 
assessments, should be recorded on the appropriate AE page of the CRF. This will assist the 
sponsor or designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
6.2.16
Electrocardiograms
A 12-lead ECG will be performed during screening, at baseline, Week 4, and at last (Week 24)
visits during Stage 2; at first visit (last visit for Stage 2) and at Months 2, 6, 12, 18, and 24 (or 
early termination) visits during Stage 3; and at end-of-study (or early termination) visit during 
Stage 4.  The ECG will be done at the study center after the subject has been resting for at least 
5 minutes.  Results will include general findings only (normal/abnormal).  Investigators are 
responsible for providing their own interpretation of the ECG and this will be captured on the 
CRF.  
Two ECG tracings should be printed, and both signed and dated by the investigator.  One tracing 
will be kept with the subject’s source documents and the second will be sent to the sponsor or 
designee.  If 2 tracings cannot be printed, the copy will be kept at the site and the original sent to 
the sponsor or designee.
6.2.17
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Schedule of 
Evaluations and Procedures (Table 6-1, Table 6-2, Table 6-3, and Table 6-4) for details and 
scheduling.


Shire
CONFIDENTIAL
Page 41
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
6.2.17.1
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization) in subjects with any colon remnant including rectal 
stump evaluation. This will be repeated at Visit 10 in Stage 2, at Visit 25 (Month 24 or early 
termination) in Stage 3, and at  end-of-study (or early termination) visit in Stage 4.  A 
colonoscopy is required at the beginning of the study, at the end of the 24-week and 24-month
treatment periods, and at the end of the study to determine if any clinically significant changes 
have occurred. The date and result of colonoscopy are to be recorded in the CRF. If a subject 
had a normal colonoscopy within 6 months prior to screening, a baseline 
colonoscopy/sigmoidoscopy will not be required.
6.2.17.2
Abdominal Ultrasound and Upper GI Contrast Series with Small Bowel 
Follow-through
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented). Upper GI contrast series with small bowel follow-through 
will be required for all subjects with a history of Crohn’s disease and will be performed during
the stabilization period, prior to the baseline visit.
6.3
Pharmacokinetic Evaluations
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0) in Stage 2 of 
the study. Samples for PK analysis will be collected pre-dose, at 15, 30 and 60 minutes post-
dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose. The site of teduglutide administration prior 
to PK blood draws (arm, thigh, abdomen) must be specified.  If PK sample collection is missed 
at Visit 2, PK sample may be collected at any visit through Visit 7. 
The following parameters will be derived:

AUC0–inf

AUC0–t

Cmax

tmax

t1/2

CL/F

V/F
6.4
Schedule of Evaluations and Procedures
All clinical study evaluations prior to treatment with teduglutide will be performed according to
the Schedule of Evaluations and Procedures – Stage 1, Table 6-1. All clinical study evaluations 
during the first 24 weeks of treatment will be performed according to the Schedule of 
Evaluations and Procedures – Stage 2, Table 6-2. All clinical study evaluations during the 
extension will be performed according to the Schedule of Evaluations and Procedures in Stage 3 
(Table 6-3) and Stage 4 (Table 6-4).


Shire
CONFIDENTIAL
Page 42
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Subjects who drop out of the study prior to the final visit should have all early termination
procedures done whenever possible. 






Shire
CONFIDENTIAL
Page 45
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
Eligibility criteria
X
Crohn’s disease assessmentc
X
Physical examinationd
X
X
X
X
X
X
X
X
Evaluation of PN/I.V.
(actual volume L/week)
Xe
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Colonoscopy/
  Sigmoidoscopy
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
Xf
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrulline
X
X
X
X
X
Antibodies to teduglutide
and E. coli proteing
X
X
X
PK sampling
Xh
(X)
(X)
(X)
(X)
(X)
Urine pregnancy test
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Interim safety evaluation
[X]i
[X]i
[X]i
[X]i
[X]i
[X]i
48-hour oral fluid intakej
(Diary)
X
X
X
X
X
X
X
X
48-hour urine outputj
(Diary)
X
X
X
X
X
X
X
X
Diary
X
X
X
X
X
X
X
X
X
Teduglutide dosingk
X
X
X
X
X
X
X
X
X
Compliancel
X
X
X
X
X
X
X
X


Shire
CONFIDENTIAL
Page 46
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 6-2
Schedule of Evaluations and Procedures – Stage 2
Procedures
Baseline
Dosing
Week 1a
Dosing
Week 2
Dosing
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing
Week 24
(or early 
terminationb)
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
Study Day
0
7
14
28
56
84
112
140
168
(X) = Possible PK sampling time point (Refer to footnote “i”.); [X ] = Possible interim safety evaluation time point (Refer to footnotes “f” and “g”.); 
BMI = body mass index; 48-hour I/O = 48-hour fluid intake/urine output; ECG = electrocardiogram; PK = pharmacokinetic; PN = parenteral nutrition; 
PN/I.V. = parenteral nutrition/intravenous fluids; V = visit
a Subject does not have to visit the clinic for visit.  Assessments will be completed over the phone.
b Subjects with an early termination visit should have all applicable Visit 10 assessments.  Call sponsor for guidance.
c Subjects with active Crohn’s disease are excluded from the study participation, therefore endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.
d A full physical examination is to be performed at baseline and Visit 10; a brief examination will be performed at all other dosing weeks with a clinic visit.
e The PN/I.V. evaluation is to confirm weekly volume for Inclusion Criteria 5 (PN/I.V. frequency) and 6 (stable PN/I.V.).
f This is the second of 2 body weight measurements that will be used to determine drug volume.
g Blood sample for antibody testing is to be collected at baseline (Visit 2) prior to first investigational product administration. Once the subject has started 
teduglutide treatment, samples must be drawn at least 14 hours after dosing.
h Samples for PK analysis are collected pre-dose, at 15, 30 and 60 minutes post-dose and at 2, 3, 4, 6, 8, 10 and 12 hours post-dose.  If PK sample collection is 
missed at Visit 2, PK sample may be collected at any visit through Visit 7. The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) 
must be specified.
i Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V.  These measures 
include 48-hour oral fluid intake, 48-hour urine output, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
j All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the scheduled visit.  The measurements should include 1 day 
on and 1 day off PN/I.V., unless PN is infused daily.
k Subjects will be trained to self-inject teduglutide at baseline on Day 0 (Visit 2).  The first injection should be administered under the supervision of the 
investigator or designee and the subject observed for at least 4 hours.  Subjects will then self-inject the study drug at home. Dosing should not take place at early 
termination visit.
l Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Shire
CONFIDENTIAL
Page 47
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First 
Visita 
(last 
visit for 
Stage 2)
Mo 
1/13b
Mo 
2/14
Mo
3/15b
Mo 
4/16
Mo 
5/17 b
Mo 
6/18
Mo 
7/19b
Mo 
8/20
Mo 
9/21b
Mo 
10/22
Mo 
11/23b
Mo 
12
Mo 24
(or early 
termi-
nation)
Visit Number:
V1
V2/
14
V3/ 
15
V4/
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days) 
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Eligibility, Informed consent
X
Reproductive status (female 
subjects)
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and BMI
X
X
X
X
X
X
X
X
Height
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
12-lead ECG
X
Xd
X
X
X
Colonoscopy/sigmoidoscopy 
of remnant colon
X
Citrulline
X
X
X
X
X
X
X 
X
Antibodies to teduglutide 
and E. coli proteine
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Xf
Interim safety visit
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
[X]g
Diaryh
X
X
X
X
X
X
X
X
48-hour oral fluid intakei  
(Diary)
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
X
48-hour urine outputi (Diary)
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
X


Shire
CONFIDENTIAL
Page 48
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 6-3
Schedule of Evaluations and Procedures – Stage 3 (Extension)
Procedures
First 
Visita 
(last 
visit for 
Stage 2)
Mo 
1/13b
Mo 
2/14
Mo
3/15b
Mo 
4/16
Mo 
5/17 b
Mo 
6/18
Mo 
7/19b
Mo 
8/20
Mo 
9/21b
Mo 
10/22
Mo 
11/23b
Mo 
12
Mo 24
(or early 
termi-
nation)
Visit Number:
V1
V2/
14
V3/ 
15
V4/
16
V5/ 
17
V6/ 
18
V7/ 
19
V8/
20
V9/ 
21
V10/
22
V11/ 
23
V12/ 
24
V13
V25
Visit Window (days) 
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Evaluation of PN/I.V. (actual 
volume L/week)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Teduglutide dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
Compliancej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
[X]=optional 48-hour oral fluid intake and urine output (Diaries) to be measured at the discretion of the investigator in consideration of PN/I.V. adjustment; 
[X]g=possible interim safety evaluation time point (Refer to footnote “g”.); BMI=body mass index; ECG=electrocardiogram; L=liter; Mo=month; 
PN/I.V.=parenteral nutrition/intravenous fluids; V=visit
Note:  Study visits will be scheduled every other month throughout the study period.  At the end of 12 months, the visit schedule will repeat starting with the 
Month 1 visit.  Interim (standard of care) visits may be utilized to assess subjects’ well-being (ie, occurrence of adverse events) and to check for any changes in 
medications.
a In case study extension treatment cannot be started at the last completed visit of Stage 2 for any reason, the investigator may repeat any assessments as deemed 
appropriate.
b Subject does not need to visit the clinic.  Assessments will be completed over the telephone.
c Full physical examination to be performed at first and last visits; a brief examination will be performed at all other study visits.
d An ECG will be taken at Visit 3, but not at Visit 15.
e Sample for antibody testing must be drawn at least 14 hours after dosing.
f Teduglutide dispensing and dosing should not be performed at early termination visit.
g Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made to the subject’s PN/I.V. volume.  
Hematocrit, serum blood urea nitrogen and serum creatinine, and urine sodium will be measured.
h The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
i All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next scheduled visit and interim safety visit.  The 
measurements should include 1 day on and 1 day off PN/I.V., unless PN/I.V. is infused daily or the subject achieves enteral autonomy (no PN/I.V. use).
j Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


Shire
CONFIDENTIAL
Page 49
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table 6-4
Schedule of Evaluations and Procedures – Stage 4 (Extension)
Procedures
Every 3-Month 
Visita
EOS
(or early termination)
Visit Number:
V26, 27, 28, etc.
EOS
Visit Window (days) 
± 7
± 7
Adverse events
X
X
Urine pregnancy test
X
X
Physical examinationb
X
X
Vital signs
X
X
Body weight and BMI
X
X
Concomitant medications
X
X
Safety laboratory tests
X
X
12-lead ECG
X
Colonoscopy/sigmoidoscopy of remnant colon
X
Citrulline
X
X
Antibodies to teduglutide and E. coli proteinc
(X)
X
Drug dispensing
X
Interim safety visit
[X]d
[X]d
Diarye
X
X
48-hour oral fluid intakef  (Diary)
X
X
48-hour urine outputf (Diary)
X
X
Evaluation of PN/I.V. (actual volume L/week)
X
X
Teduglutide dosing
Xg
Complianceh
X
X
(X)=assessment to be performed only every other visit (every 6 months); [X]d=possible interim safety evaluation 
time point (Refer to footnote “d”); BMI=body mass index; ECG=electrocardiogram; EOS=end of study; L=liter; 
PN/I.V.=parenteral nutrition/intravenous fluids; V=visit
Note:  Study visits will be scheduled every 3 months throughout the Stage 4 period. Interim (standard of care) visits 
may be utilized to assess subjects’ well-being (ie, occurrence of adverse events) and to check for any changes in 
medications.
a Subjects will undergo a clinic visit every 3 months until teduglutide is commercially available for each subject, the 
subject’s participation in this study is discontinued, or the study is discontinued.
b Full physical examination to be performed at end-of-study (or early termination) visit; a brief examination will be 
performed at all other study visits.
c Sample for antibody testing must be drawn at least 14 hours after dosing. To be collected at every other visit only 
(every 6 months) and end-of-study (or termination) visit.
d Interim safety evaluations will be performed 5 to 7 days after any scheduled visit when a reduction has been made 
to the subject’s PN/I.V. volume.  Hematocrit, serum blood urea nitrogen and serum creatinine, and urine sodium will 
be measured.
e The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
f All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the next 
scheduled visit and interim safety visit.  The measurements should include 1 day on and 1 day off PN/I.V., unless 
PN/I.V. is infused daily or the subject achieves enteral autonomy (no PN/I.V. use).
g The dose of study drug administered at time of entry into Stage 4 (Visit 26) may be adjusted based on change in 
the subject’s weight from baseline.
h Compliance will be checked at every visit by asking subjects if they have taken their study drug according to 
instructions and by performing drug accountability.


Shire
CONFIDENTIAL
Page 50
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
DATA MANAGEMENT
7
7.1
Data Collection
Upon entry into the study (informed consent signed), all subjects will be assigned an eight-digit 
subject number.  The first 4 digits consist of the study site number.  The last 4 digits will be 
assigned sequentially starting with 0001.  This number is the main identifier for subjects.
The site staff will keep records of the subject’s visit in the files considered as source documents 
for that site (eg, hospital chart, research chart, etc.). Source data are all information contained in 
original records of clinical findings, observations, or other trial-related activities necessary for 
evaluation and reproducibility of data (eg, progress notes, hospital records, computer print-outs, 
screening logs, and recorded data from automated instruments). In case of computerized source 
data, the investigator has to give the sponsor access to the subject files at each monitoring visit. 
The data is then entered into the Electronic Data Capture System, RAVE.  To ensure that data 
have been entered correctly on the electronic case report forms (eCRF), they will be 100% 
source-data verified by a monitor from the sponsor/designee, who will notify the investigator 
regarding any questions or discrepant data. The investigator or designee will be responsible for 
the timely recording of subject data into the eCRF.
The investigator and study site must permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents.
The principle investigator (PI) or designee will review all eCRFs (including the termination page 
after the subject’s final visit) for completeness and accuracy, and will sign the eCRF via an 
electronic signature. The PI will be responsible for reviewing the data in a timely manner.  
Non-CRF data will be sent to the sponsor or designee via a data transfer from the appropriate 
vendor for assimilation into the database. 
Paper diaries will be used by the subjects to record study information, which includes PN/I.V.
infusions, drug dosing, and 48-hour I/O. Standardized procedures will be used to incorporate 
these data into the clinical database. 
The sites will be provided with CRF guidelines outlining the specific procedures to use when 
entering the data into the Electronic Data Capture System. Data validation and edit checks will 
be conducted on the data. Any discrepancies will generate queries that should be resolved at the 
study site in a timely manner.  The audit trail will be recorded in the data base.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor or designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.


Shire
CONFIDENTIAL
Page 51
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
An audit of the clinical database will be performed. When all issues from the audit are resolved, 
and all data management processes are completed for finalizing the database, the database will 
be ready for statistical analysis by the sponsor or designee. 
7.2
Record Retention
All source documents, records, and reports will be retained by the clinical center/investigator in 
accordance with ICH guidelines. These documents include all primary data or copies thereof 
(eg, laboratory records, ECGs, data sheets, correspondence, photographs, and computer records), 
which are a result of the original observations and activities of the study and are necessary for 
the reconstruction and evaluation of any study report.
All source documents, records, and reports should be retained for a period of not less than 
15 years from completion of the clinical trial.  The sponsor will notify site staff of permission to 
dispose of them. 
7.3
Quality Control
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. 
Medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical 
classification) and preferred name using the World Health Organization Drug Dictionary.
The study data will be captured by the investigational site staff on CRFs.  The staff will keep 
records of the subject’s visit in the files considered as source documents for that site.
Study information on PN/I.V. infusions and 48-hour I/O will be recorded by the subjects in 
subject diaries.  These data are regarded as source data and will remain at the site.  The relevant 
information will be recorded in the CRF at each study visit.
To ensure that data have been entered correctly on the CRF, they will be 100% source-data 
verified by a monitor from the sponsor/designee, who will notify the investigator regarding any 
questions or discrepant data.  Data validation and edit checks will be conducted by the sponsor or 
designee.  Any discrepancies noted will generate queries.  Upon receipt of the query via the 
electronic data capture (EDC) system, the site will research the issue identified on the query and 
record the answer in EDC.  In the event that the appropriate individual at the site provides an 
incorrect, incomplete, or inappropriate response, the query will be re-issued to the site.  When all 
subjects’ data have been entered into the database, verified, and all outstanding issues have been 
resolved with the site, the data will be evaluated for quality purposes.  A clean file of the data is 
defined as when the data in the database and the reference values are complete and logical 
according to the protocol, general guidelines, and data management plan.  Once the sponsor or 
designee acknowledge that all data are acceptable, the data will be declared a “clean file,” and 
the database will be frozen/hard locked.  At the end of the study, each site will receive a compact 
disc containing their data.


Shire
CONFIDENTIAL
Page 52
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
STATISTICAL METHODOLOGY 
8
8.1
Demographic and Baseline Variables
Demographic variables include age; gender; race; height; body weight; BMI; intestinal length; 
presence or absence of a stoma, colon in continuity, ileocecal valve; and time since last surgical 
resection. 
Descriptive statistics (eg, number, mean, standard deviation, median, minimum and maximum 
values, and the number and percentage of subjects in specified categories) will be used to 
summarize the baseline and demographic characteristics.  Individual data will also be listed.
8.2
Efficacy and Pharmacodynamic Variables
No formal testing will be conducted for efficacy or pharmacodynamic variables.  For continuous 
variables, descriptive statistics will be used to summarize median, maximum, minimum, mean 
(± standard deviation [SD]), geometric mean (± standard error [SE]) and its 95% confidence 
interval (CI).  For categorical variables n (%) will be summarized.  Listings of individual data 
will be summarized.
PK parameter estimates will be calculated using a non-compartmental analysis.
8.2.1
Efficacy and Pharmacodynamics – Stage 2
The efficacy endpoints are: 

Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks (by 
visits and EOT).  Weekly PN/I.V. volume will be based on the subject diary recordings.

Percentage of subjects who demonstrate a response at Week 20 and again at Week 24 in 
Stage 2 of the study (responder).  A response is defined as the achievement of at least a 20% 
reduction from baseline (Visit 2) in weekly PN/I.V. volume.

Change in days per week of PN/I.V. support

Changes in plasma citrulline from baseline to Week 24 (or EOT)
In this uncontrolled study, efficacy will be described by the following assessments:

Comparison of the mean PN/I.V. percent change at Week 24 with the upper limit of the 95% 
CI (of least square [LS] mean) for the teduglutide group in pivotal Phase 3 
Study CL0600-020 at Week 24.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from US/EU pivotal controlled Phase 3 
Study CL0600-020.  The comparison should take into account the anticipated variability of 
the data due to the small number of subjects in Study TED-C14-004.

Comparison of the upper limit of the 95% CI of the mean percent change in weekly PN/I.V. 
volume at Week 24 with the mean change in PN/I.V. volume at Week 24 in the placebo 
group in Study CL0600-020.  As Study TED-C14-004 is an uncontrolled study, PN/I.V. 
results will be compared with those from Study CL0600-020.  The comparison should take 


Shire
CONFIDENTIAL
Page 53
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the mean PN/I.V. percent change at Week 24 with the lower limit of the 95% 
CI (of LS mean) for the teduglutide group in pivotal Phase 3 Study CL0600-020 at Week 24.  
As Study TED-C14-004 is an uncontrolled study, PN/I.V. results will be compared with 
those from US/EU pivotal controlled Phase 3 Study CL0600-020.  The comparison should 
take into account the anticipated variability of the data due to the small number of subjects in 
Study TED-C14-004.

Comparison of the responder rate with the primary endpoint responder rate of the placebo 
group observed in Study CL0600-020.  (The percentage of subjects who achieved ≥20% 
PN/I.V. reduction from baseline at Week 20 and Week 24 in the placebo group was 30.2%.)

Evaluation of the change in days off PN/I.V. per week.  In general, day(s) off PN/I.V. cannot 
be expected in this subject population, which has required long-term PN/I.V., unless 
absorption is increased by teduglutide.

Evaluation of the number of subjects who achieve complete enteral autonomy (wean off) of 
PN/I.V. during the study.  In general, weaning off PN/I.V. cannot be expected in this subject 
population, which has required long-term PN/I.V., unless absorption is increased by 
teduglutide.
8.2.2
Efficacy and Pharmacodynamics – Stages 3 and 4
Absolute and percent change from baseline in weekly PN/I.V. volume and changes in days per 
week of PN/I.V. support and plasma citrulline levels will continue to be evaluated throughout the 
long-term extension.
8.3
Safety
The safety and tolerability of teduglutide treatment will be assessed by evaluation of TEAEs, 
12-lead ECGs, vital signs, GI-specific testing, laboratory safety data, antibodies to teduglutide, 
and changes in urine output, body weight, and BMI.  See Section 6.2 for a full list of safety 
variables.
8.3.1
Statistical Methods for Safety Variables
Adverse events will be coded using the most recent version of the MedDRA dictionary. 
Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity, relationship to treatment, AEs leading to discontinuation, and AEs 
leading to death. SAEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, and ECG variables, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from Baseline at each time point. 


Shire
CONFIDENTIAL
Page 54
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.
8.4
Pharmacokinetic Variables – Stage 2 Only
Single-dose PK will be evaluated on the first day of teduglutide treatment (Day 0).  
Pharmacokinetic variables include AUC0–inf, AUC0–t, Cmax, tmax, t1/2, CL/F, and V/F.  
Pharmacokinetic parameter estimates will be calculated using a non-compartmental analysis.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were enrolled into the study
and eligible to enter stage 2. The safety population is defined as the subset of ITT with subjects 
who received at least one administration of study drug with any safety follow up. The primary 
population analyzed for efficacy will be the ITT population. An additional per-protocol population 
analysis may also be performed as secondary/sensitivity analysis. Applicable analysis populations 
will be defined in the Statistical Analysis Plan (SAP).
8.6
Statistical/Analytical Issues
8.6.1
Adjustments for Covariates
No baseline stratification parameter is employed in this study.
8.6.2
Handling of Dropouts or Missing Data
All subjects enrolled will be included in the analyses. Missing safety parameters will not be 
imputed. The weekly PN/I.V. volume recorded in the subject diaries will be calculated in 
2-week intervals. Missing daily PN/I.V. volumes from subject diaries will not be imputed and a 
maximum of 5 missing days (or at least 9 days of non-missing data) from the 14-day intervals 
are allowable, or else the interval will be classified as missing. Details for the imputation 
algorithm for the missing endpoint values for PN/I.V. volume will be detailed in the SAP.
8.6.3
Interim Analyses
An interim analysis of study data will be done at the completion of the 24-week Stage 2 part of 
the study and again after subjects complete 6 months of treatment in the Stage 3 extension period 
(1 year of teduglutide exposure).  A final analysis of study data will be done at the end of the 
study.
8.6.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be no 
adjustment for alpha level.
8.6.5
Use of an Efficacy Subset of Subjects
All subjects will be included in the analysis.


Shire
CONFIDENTIAL
Page 55
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
8.6.6
Examination of Subgroups
Not applicable
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final Clinical Study Report (CSR).
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 [5th revision], Notes of Clarification added 
by the WMA General Assembly in Washington 2002 and in Tokyo 2004, and Seoul 
[6th revision]).
In accordance with guidelines, the protocol, any advertisements, and ICFs (or assent form, if 
applicable) will be reviewed and approved by the IRB. The sponsor will supply relevant 
materials for the investigator to prepare a written ICF and submit to the IRB for the 
protocol/ICF’s review and approval. Verification of the IRB approval of the protocol and the 
written informed consent statement will be forwarded to the sponsor (or designee).
The investigator will inform the IRB of subsequent protocol amendments and any SUSARs if the 
sponsor has assessed it as an unanticipated problem.  Approval for protocol amendments will be 
transmitted in writing to the investigator. The investigator will provide the IRB with progress 
reports at appropriate intervals (not to exceed one year) and a study summary report following 
the completion, termination, or discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written subject information/ICF approved by the IRB and signed by the subject before protocol-
specific procedures are performed. When the subjects are under 20 years old, written informed 
consent must be obtained from the subject’s parent(s) or legally authorized representative(s) after 
confirming assent from the subject.  A subject information/ICF model will be provided by the 


Shire
CONFIDENTIAL
Page 56
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
sponsor or designee and adapted by the investigator in agreement with the sponsor to meet 
center, state, and country ethical guidelines, as appropriate.
The investigator (or designee) will explain to the subject the nature of the study and the action of 
the test product, and any risks and benefits. The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care. 
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should be 
informed in writing that their data will be stored and analyzed in a computer, with confidentiality 
maintained in accordance with national and local legislation. Site-specific information must be 
added to the ICF as appropriate.
Subjects should also be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records (relevant to the study), including medical history, for data verification.
The PI is responsible for keeping a subject identification list of all subjects screened and enrolled 
which includes the following information: subject number, full name, and a secondary unique 
identifier (ie, hospital/clinic number).
9.4
Payment and Compensation
The special or specified medical care system covers the treatment periods.  The sponsor and the 
trial site will discuss payment for cooperating in this clinical trial.  IRB-approved expenses will 
be paid by the sponsor to the subject thorough the trial site.
The sponsor will provide insurance or indemnify the subject against claims arising from this 
clinical trial, except for claims that arise from malpractice and/or negligence.
9.5
Changes to the Protocol
No change in the study procedures shall be affected without the mutual agreement of the sponsor 
and the investigator. All changes must be documented as signed protocol amendments or as a 
revised protocol. Changes to the protocol may require notification to or approval by the IRB and 
the regulatory authorities before implementation. Local regulatory requirements must be 
followed. Instructions for reporting deviations from the protocol can be found in the study 
reference manual.


Shire
CONFIDENTIAL
Page 57
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the PI
and those concerned within the conduct of the study. The sponsor and PI are responsible for 
reporting all amendments to the IRB. 
9.6
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor. These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
or for submission to regulatory agencies. In addition, the sponsor reserves the right of prior 
review of data from this study relative to the potential release of proprietary information to any 
publication or for any presentation.
This clinical study will be registered on www.ClinicalTrials.gov and the results will be disclosed 
on www.ClinicalStudyResults.org.
9.7
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


Shire
CONFIDENTIAL
Page 58
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
REFERENCES
10
None


Shire
CONFIDENTIAL
Page 59
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
APPENDIX 1
PN/I.V. OPTIMIZATION (STAGE 1)
After signing the ICF, the investigator will determine if the subject’s PN/I.V. volume produces 
an appropriate urine output target of 1.0 to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/I.V. 
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 to 
2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 48-hour 
urine output is:

< 1.0 L/day, then PN/I.V. should be increased.

> 2.0 L/day, then PN/I.V. should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/I.V. volume should be documented.  Keep in 
mind the following:

Total weekly PN/I.V. volume can be adjusted by up to 30% of the current volume.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/I.V. volume:
1.
Screening and Optimization Visits: Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  The measurements should include 1 day on and 
1 day off PN/I.V. unless subject infuses PN/I.V. daily.  Blood and urine samples will be 
collected at each visit to evaluate hydration and nutrition.  All blood and urine samples 
should be taken at a consistent time period throughout the study that is convenient for the 
subject and site staff.
2.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and 
the health status of the subject will be assessed after 5 to 7 days of the adjustment.  
Laboratory safety samples should be evaluated following a PN/I.V. adjustment (see 
Table A2-3), accompanied by determination of 48-hour I/O and symptoms of dehydration.  
At the interim safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No 
further reductions to PN/I.V. volume are made at the interim safety visit.
3.
Maintain the PN/I.V. level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/I.V. indicated 
by targeted urine output of 1.0 to 2.0 L/day.  If a subject has not achieved an optimal 
tolerated volume of PN/I.V. after 8 weeks, consult the sponsor’s Medical Monitor.


Shire
CONFIDENTIAL
Page 60
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
5.
PN/I.V. Stabilization: Once an optimal tolerated PN/I.V. volume has been reached, the 
subject will begin the 4-week minimum stabilization period. No further PN/I.V. adjustments 
should take place during this time period.


Shire
CONFIDENTIAL
Page 61
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
APPENDIX 2  PN/I.V. ADJUSTMENT DURING DOSING (MAIN TREATMENT 
PERIOD – STAGE 2)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

There will be no PN/I.V. reduction attempts at baseline and Week 1.

PN/I.V. reductions target urine output increases of at least 10% over baseline.

Attempts to reduce PN/I.V. will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of stabilized 
baseline PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A2-1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo 1 additional attempt to reduce 
volume by at least 10%.

Subjects who fail to maintain a PN/I.V. reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical Monitor.
Table A2-1 PN/I.V. Adjustments based on 48-hour Urinary Output
Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on stabilized 
urine output
Increase PN/I.V. by at least 10% (Week 2) or to previous level.
1.0 L/day or more and less than Baseline
If subject is dehydrated or inadequately nourished (see Table A2-
2), increase PN/I.V.  If not, maintain PN/I.V.
Baseline or more, and less than a 10% increase 
over Baseline
Maintain PN/I.V.
At least a 10% increase over Baseline
Reduce PN/I.V. by at least 10% of stabilized Baseline level up to 
a clinically appropriate amount (maximum of 30%).
L = liter; PN/I.V. – parenteral nutrition/intravenous (volume)


Shire
CONFIDENTIAL
Page 62
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table A2-2  Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
*AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A2-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.
Steps for adjusting PN/I.V. volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20: Subjects will be assessed at planned intervals 
for hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  The measurements should include 1 day on and 1 day off 
PN/I.V. unless subject infuses PN/I.V. daily or achieves enteral autonomy (no PN/I.V. use).  
Blood and urine samples will be collected to evaluate hydration and nutrition (see Table A2-
2).  All blood and urine samples should be taken at a consistent time period throughout the 
study, convenient for the subject and site staff.
2.
PN/I.V. Changes: Review Table A2-1 and Table A2-2 to take appropriate action. 
(Reduction of PN/I.V. by 10% or more of the baseline volume is called a “challenge.”)
3.
Interim Safety Evaluations: If any PN/I.V. adjustments are made, the clinical effect and 
the health status of the subject will be assessed 5 to 7 days after the adjustment.  Laboratory 
safety samples should be evaluated following a PN/I.V. adjustment (see Table A2-3), 
accompanied by determination of 48-hour I/O and symptoms of dehydration.  At the interim 
safety visit, PN/I.V. should be increased if the decrease was not tolerated.  No further 
reductions to PN/I.V. volume are made at the interim safety visit.


Shire
CONFIDENTIAL
Page 63
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table A2-3  Targeted PN/I.V. Adjustments at Interim Visits
Urine Output, Hydration and Nutrition
PN/I.V. Action
Output less than Baseline
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is dehydrated (See 
Table A2-2)
Increase PN/I.V. to previous volumea
Baseline output or greater and subject is not dehydrated, but 
is inadequately nourished (See Table A2-2)
If possible, maintain PN/I.V. volume and increase 
nutrition. If not, increase PN/I.V. to previous 
volumea
Baseline output or greater and subject is adequately hydrated 
and nourished (See Table A2-2)
Maintain PN/I.V.
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume)
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate 
increase in PN/I.V. is allowed.
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
Subjects who did not tolerate the reduction may be re-challenged at the next visit 
provided they meet the criteria for adequate hydration and nutrition.  
d.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Shire
CONFIDENTIAL
Page 64
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
APPENDIX 3
PN/I.V. ADJUSTMENT DURING DOSING (EXTENSION 
TREATMENT PERIOD – STAGE 3 AND STAGE 4)
Points to keep in mind when adjusting PN/I.V. volume during dosing:

PN/I.V. volume reductions target urine output increases of at least 10% over Baseline. 
Baseline measurements for all subjects are taken at the baseline of study main treatment 
period.

Considerations to reduce PN/I.V. will be made at all planned visits.

PN/I.V. adjustments are targeted to be at least 10% but no more than 30% of STABILIZED 
BASELINE PN/I.V. level.

Adjustments should be based on the actual PN/I.V. volume the subject infuses. Subjects 
should remain compliant with the PN/I.V. prescription during the length of the study.

PN/I.V. constituents may be adjusted at the discretion of the investigator.

Criteria for PN/I.V. adjustments are in Table A3-1.

During the 48-hour I/O measurement period, oral intake should be consistent with Baseline 
oral intake or greater.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/I.V. volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Checks will be made to ensure the adjustments are safe (see Table A3-2).

Subjects who fail to maintain a PN/I.V. reduction may undergo additional attempts to reduce 
volume by at least 10%.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical Monitor.
Table A3-1 PN/I.V. Adjustments Based on 48-hour Urinary Output
48-hour Urine Output
PN/I.V. Action
Below 1.0 L/day or target based on stabilized 
urine output
Increase PN/I.V. by at least 10% or to previous level.
1.0 L/day or more and less than Baseline
If subject is dehydrated or inadequately nourished (see Table A3-
2), increase PN/I.V.  If not, maintain PN/I.V.
Baseline or more, and less than a 10% increase 
over Baseline
Maintain PN/I.V.
At least a 10% increase over Baseline
Reduce PN/I.V. by at least 10% of stabilized Baseline level up to 
a clinically appropriate amount (maximum of 30%).
L = liter; PN/I.V. = parenteral nutrition/intravenous (volume)
Steps for adjusting PN/I.V. volume:
1.
Subjects will be assessed at planned intervals for hydration and nutrition.  The subject will 
make all measurements of 48-hour I/O at home prior to the scheduled visits.  The 


Shire
CONFIDENTIAL
Page 65
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
measurements should include 1 day on and 1 day off PN/I.V. unless subject infuses PN/I.V. 
daily or achieves enteral autonomy (no PN/I.V. use).  All blood and urine samples should be 
taken at a consistent time period throughout the study, convenient for the subject and site 
staff.
2.
PN/I.V. CHANGES: Review Table A3-1 and Table A3-2 to take appropriate action. 
3.
If any PN/I.V. adjustments are made, the clinical effect and the health status of the subject 
will be assessed 5 to 7 days after the adjustment.  Laboratory safety samples should be 
evaluated following a PN/I.V. adjustment, accompanied by determination of 48-hour I/O and 
symptoms of dehydration.  At the interim safety visit, PN/I.V. should be increased if the 
decrease was not tolerated.  No further reductions to PN/I.V. volume are made at the interim 
safety visit. After the first 3 months of the extension treatment period, the assessment of 
laboratory values is not mandatory anymore at interim safety visits. 
4.
Maintain the adjusted PN/I.V. level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/I.V. needs have been reduced to a level that 
safely allows for a day or days off PN/I.V., the physician should consider instituting a 
day(s) off PN/I.V.
b.
If the total weekly PN/I.V. is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/I.V. completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra I.V. fluid that will be included in the weekly PN/I.V. volume 
total.


Shire
CONFIDENTIAL
Page 66
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
Table A3-2 Targeted Criteria for Hydration and Nourishment
Hydration Assessment
Hydration Adequate*
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/day or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
* AND consistent with subject’s previous levels prior to study entry.
Note: In combination with Table A3-1, any one of the above criteria determines dehydration.
Note: If weight gain of ≥1.5 kg, request physician review.


Shire
CONFIDENTIAL
Page 67
TED-C14-004 Protocol Amendment 4
Teduglutide
Version 6.0 / 03 Apr 2017
APPENDIX 4
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics Committee 
(IRB) for the study protocol and any amendments thereof, written informed consent or updates 
thereof, subject recruitment procedures (eg, advertisements), and any other written information 
to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from 
the sponsor and review and documented approval from the IRB, except to eliminate an 
immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or In-country 
Clinical Caretaker including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date 
(DD MMM YYYY)



SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
Protocol TED-C14-004 
 
A 4-Stage Open-label, Multicenter Study Including Long-term Extension 
to Evaluate the Safety, Efficacy and Pharmacokinetics of Teduglutide in 
Japanese Subjects with PN-dependent Short Bowel Syndrome 
 
 
 
 
 
 
Protocol Issued:  03 April 2017 
 
Version 6.0   Amendment 4.0               
 
 
 
Statistical Analysis Plan:        29 October 2018 
Version 2.0 
 
 
 




Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 2 of 35 
 
Version 2.0 
  
Document History 
 
Version/Date 
History 
Version 1.0 / 05 October 2012 
Original Document 
Version / 01 December 2016 
Statistical Analysis Plan for the 12-Month interim 
analysis 
Version 2.0 / 29 October 2018 
Updated SAP to incorporate Stage 4 data for the 
final CSR 
 
 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 3 of 35 
 
Version 2.0 
  
TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................3 
ABBREVIATIONS ............................................................................................................5 
1 
INTRODUCTION AND BACKGROUND INFORMATION ......................7 
2.1 
Study Design .......................................................................................................7 
2.2 
Objective ...........................................................................................................10 
2.2.1 
Efficacy and Pharmacodynamic Endpoints – Stage 2 .................................10 
2.2.2 
Efficacy and Pharmacodynamic Endpoints – Stages 3 and 4 .....................10 
2.2.3 
Pharmacokinetic Endpoints – Stage 2 Only .................................................10 
2.2.4 
Safety Objectives .............................................................................................10 
2 
DETERMINATION OF SAMPLE SIZE .....................................................11 
3 
UNBLINDING PROCEDURES ....................................................................11 
4 
DATA MANAGEMENT ................................................................................11 
5 
STATISTICAL/ANALYTICAL ISSUES .....................................................11 
6.1 
General Methodology........................................................................................11 
6.2 
Adjustments for Covariates/Prognostic Variables ............................................12 
6.3 
Handling of Dropouts or Missing Data .............................................................12 
6.4 
Interim Analyses and Data Monitoring .............................................................12 
6.5 
Multicenter Studies ...........................................................................................12 
6.6 
Multiple Comparisons/Multiplicity ...................................................................12 
6.7 
Active-Control Studies Intended to Show Equivalence ....................................12 
6.8 
Examination of Subgroups ................................................................................13 
6 
ANALYSIS POPULATIONS AND VISITS .................................................13 
7.1 
Efficacy/PD Analysis Populations ....................................................................13 
7.2 
Safety Analysis Population ...............................................................................13 
7.3 
PK Analysis Population (Stage 2 Only) ............................................................13 
7.4 
Windowing Visits .............................................................................................14 
7 
STUDY SUBJECTS ........................................................................................14 
8.1 
Subjects Screened and Enrolled ........................................................................14 
8.2 
Study Analysis Populations ..............................................................................14 
8.3 
Protocol Deviations ...........................................................................................14 
8.4 
Disposition of Subjects .....................................................................................14 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 4 of 35 
 
Version 2.0 
  
8 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....14 
9.1 
Analysis of Demographic and Other Baseline Characteristics .........................14 
9 
MEASUREMENTS OF TREATMENT COMPLIANCE ..........................17 
10 
EFFICACY/PHARMACODYNAMIC EVALUATION .............................17 
11.1 
Analysis of Efficacy and Pharmacodynamic Variables ....................................17 
11 
PHARMACOKINETIC EVALUATION .....................................................19 
12 
SAFETY EVALUATION ...............................................................................19 
13.1 
Extent of Exposure ............................................................................................21 
13.2 
Adverse Events..................................................................................................21 
13.3 
Clinical Laboratory Evaluation .........................................................................23 
13.4 
Vital Signs .........................................................................................................25 
13.5 
ECG Variables ..................................................................................................25 
13.6 
Physical Examination ........................................................................................26 
13.7 
Antibodies to Teduglutide and Escherichia coli Protein (ECP) ........................26 
13.8 
Prior and Concomitant Medications..................................................................26 
13 
CHANGES TO THE STATISTICAL METHODOLOGY PRESENTED IN 
THE PROTOCOL ..........................................................................................27 
14 
GENERAL PROGRAMMING INFORMATION .......................................27 
15.1 
General ..............................................................................................................27 
15.2 
Format of Tables/Listings .................................................................................27 
15.3 
Data Formats .....................................................................................................28 
15 
LISTINGS OF TABLE, FIGURE AND DATA LISTINGS .......................29 
16.1 
List of Tables.....................................................................................................29 
16.2 
List of Figures ...................................................................................................33 
16.3 
List of Data Listings ..........................................................................................33 
16 
TABLE, FIGURE AND DATA LISTING SHELLS ...................................34 
17.1 
Table Shells .......................................................................................................34 
17.2 
Figure Shells .....................................................................................................34 
17.3 
Data Listing Shells ............................................................................................34 
 
 
 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 5 of 35 
 
Version 2.0 
  
 
ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0–inf 
Area under the plasma concentration–time curve of zero to infinity  
AUC0-t 
AUC from zero to the last measurable concentration 
CCK 
Cholecystokinin 
Cmax 
Maximum plasma concentration 
CL/F 
Apparent clearance 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECP 
Escherichia coli protein 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
GLC 
Gas liquid chromatography 
GLP-2 
Glucagon-like peptide 2 
IB 
Investigator’s Brochure 
IBD 
Inflammatory bowel disease 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
Mass spectrometry 
NOAEL 
No Observed Adverse Effect Level 
 
 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PN 
Parenteral nutrition 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 6 of 35 
 
Version 2.0 
  
SBS 
Short bowel syndrome 
SC 
Subcutaneous 
SMT 
Safety Management Team  
SOT 
Start of Treatment 
SUSAR 
Suspected, unexpected, serious, adverse reaction 
t1/2λz 
Terminal phase half-life 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
Vλz/F 
WHODD 
Apparent volume of distribution 
World Health Organization Drug Dictionary 
WMA 
World Medical Association 
 
 
 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 7 of 35 
 
Version 2.0 
  
1  
INTRODUCTION AND BACKGROUND INFORMATION 
2.1  Study Design 
This is an open-label, multicenter, 4-stage study consisting of an optimization/stabilization 
period (Stage 1), a 24-week treatment period in which all subjects will receive teduglutide 
0.05 mg/kg/day (Stage 2), and a long-term extension (Stages 3 and 4). 
At least 5 subjects may be enrolled during the recruitment period, which ends approximately 
6 months after the initiation of the study.  
 Main Treatment Period (Stages 1 and 2) 
Stage 1 will include a screening visit; a maximum 8-week PN/I.V. optimization period (if 
required); and a stabilization period that demonstrates stable PN/I.V. support for a minimum 
of 4 weeks to a maximum of 8 weeks.  
If at screening a subject does not have a stable PN/I.V volume, defined as a 48-hour urine 
output within 2 to 4 L, he/she will enter the optimization period, during which the minimally 
tolerated stable PN/I.V. volume will be determined during a period of up to 8 weeks. If it is 
not possible to keep the subject adequately hydrated and nourished within the target urine 
output range, the minimally tolerated PN/I.V. volume will be documented. 
All subjects will then enter the stabilization period, during which the target volume will be 
maintained for at least 4 consecutive weeks (8 weeks maximum) prior to entering the dosing 
period (Stage 2). 
If a subject fails to maintain a stable PN/I.V. volume for at least 4 consecutive weeks, the 
subject may start the optimization period again, beginning with Week 2 (Visit 1.1). Those 
subjects who fail to stabilize after 2 attempts will not proceed further and will not be included 
in Stage 2. 
Stage 2 will be a 24-week dosing period, during which subjects will self-administer 
teduglutide 0.05 mg/kg/day at home. Stage 2 will begin with baseline assessments of 
hydration and nutritional status once the subjects have demonstrated PN/I.V. stability for 4 to 
8 weeks. At least 5 subjects will be enrolled. The on-treatment study visits will occur at 
Weeks 2, 4, 8, 12, 16 and 20, with the last scheduled visit at Week 24 of Stage 2. 
Extension Treatment Period (Stages 3 and 4) 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 8 of 35 
 
Version 2.0 
  
Stages 3 and 4 constitute the long-term extension portion of the study. Stage 3, which will 
begin immediately following Stage 2, will include subjects who complete the main treatment 
period and who are willing to continue with treatment teduglutide 0.05 mg/kg/day SC for up 
to an additional 24 months. In Stage 4, which will begin immediately following Stage 3, 
subjects will continue treatment with teduglutide 0.05 mg/kg/day SC in Study TED-C14-004 
until teduglutide is commercially available for each subject, the subject’s participation in 
this study is discontinued, or the study is discontinued. 
Any subject who achieves complete independence from PN/I.V. support at any time during 
the Stages 2, 3 or 4 treatment periods will continue to receive teduglutide treatment. If a 
subject relapses following achievement of PN/I.V. independence, PN/I.V. support will be re-
initiated and the subject will continue receiving teduglutide. 
A schematic representation of the study design is displayed in Figure 1. 
The Schedule of Evaluations and Procedures for each stage are outlined in Section 6.4 of the 
protocol.  


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 9 of 35 
 
Version 2.0 
  
Figure 1  Study Diagram 
 
 
 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 10 of 35 
 
Version 2.0 
  
2.2  Objective 
The objectives of this clinical study are to evaluate the safety, efficacy and pharmacokinetics 
of teduglutide in Japanese subjects with PN/I.V.-dependent SBS over a 24-week period 
(Stage 2) followed by a long-term extension (Stages 3 and 4) to evaluate safety and 
continued efficacy. 
 
2.2.1 Efficacy and Pharmacodynamic Endpoints – Stage 2 
 
The efficacy endpoints are as follows: 
• Absolute and percent change from baseline in weekly PN/I.V. volume over 24 weeks 
(by visits and at end of treatment [EOT]). Weekly PN/I.V. volume will be based on 
the subject diary recordings. 
• Percentage of subjects who demonstrate a response at Week 20 and again at Week 24. 
A response is defined as the achievement of at least a 20% reduction from baseline 
(Visit 2) in weekly PN/I.V. volume. 
• Change in days per week of PN/I.V. support 
• Changes in plasma citrulline levels from baseline to Week 24 (or EOT) 
 
 
2.2.2 Efficacy and Pharmacodynamic Endpoints – Stages 3 and 4 
For Stages 3 and 4, absolute and percent change from baseline in weekly PN/I.V. volume and 
changes in days per week of PN/I.V. support and plasma citrulline levels will continue to be 
evaluated throughout the long-term extension. 
 
 
2.2.3 Pharmacokinetic Endpoints – Stage 2 Only 
Pharmacokinetic Endpoints are described and analyzed in the interim report.   
 
2.2.4 Safety Objectives 
The safety and tolerability of teduglutide treatment will be assessed by evaluation of adverse 
events (AEs); 12-lead electrocardiogram (ECG); vital signs; laboratory safety data; 
antibodies to teduglutide and to Escherichia coli protein (ECP) and changes in 48-hour urine 
output, body weight and body mass index (BMI).  An abdominal ultrasound and 
colonoscopy/sigmoidoscopy of remnant colon will be done during the stabilization period if 
these procedures were not performed during the 6 months prior to screening.  
Colonoscopy/sigmoidoscopy will be repeated at the end of the main treatment period 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 11 of 35 
 
Version 2.0 
  
(Stage 2) and at the end of the extension treatment period (Stage 3 and 4).  For all subjects 
with a history of Crohn’s disease, an upper GI contrast series with small bowel 
follow-through will be performed during the stabilization period, prior to the baseline visit. 
2  
DETERMINATION OF SAMPLE SIZE 
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.    
3  
UNBLINDING PROCEDURES 
No unblinding procedures apply as this is an open-label study. 
4  
DATA MANAGEMENT 
Clinical data are collected using eCRF and data are processed by a clinical research 
organization (CRO).   
Details about data management, including the eCRF design, the EDC system, data validation 
and discrepancy management, reconciliation of data from different sources, and electronic 
data transfer, are included in the Data Management Plan for this study.  
5  
STATISTICAL/ANALYTICAL ISSUES 
6.1  General Methodology 
All statistical procedures will be completed using SAS version 9.2 or later. 
The small sample size resulting from the small study population requires the use of 
descriptive statistics with a goal of summarizing the sample and thus discourages the use of 
inferential statistics. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, 
standard deviation, maximum, and minimum.  For categorical variables, statistical summaries 
will include number of subjects and percentages. 
For summary purposes, the baseline value will be defined as the last available pre-dose value.  
Scheduled visits will be summarized as provided in the electronic case report forms (eCRFs). 
An End of Treatment (EOT) time point, defined as the last determination of endpoint or last 
available measurement from the date of first dose, will be analyzed in addition to the 
scheduled visits.  


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 12 of 35 
 
Version 2.0 
  
Study Day will be calculated as the date of the evaluation minus the date of the first day of 
study medication for study days before the first day of study medication, and the date of the 
evaluation minus the date of the first day of study medication plus one otherwise.   
All summaries will be presented by one group, unless otherwise specified. Subjects in the 
eCRF database who were not treated with study medication will be included in the 
disposition table as “Enrolled”. For subject data listings, these subjects will be listed in a 
treatment group specified as ‘Not Treated’. 
6.2  Adjustments for Covariates/Prognostic Variables 
No adjustments for covariates are planned in the statistical analyses.   
6.3  Handling of Dropouts or Missing Data 
All subjects in the analysis population defined in Sections 7.1, 7.2 and 7.3 will be included in 
the associated analyses.   
Missing safety parameters will not be imputed. 
Details on how to handle partial dates for adverse events and prior/concomitant medications 
will be discussed under Safety Evaluation. 
6.4  Interim Analyses and Data Monitoring 
There was one interim analysis of study.  A final analysis of study data will be done at the 
end of the study.   
 
6.5  Multicenter Studies 
Because a small number of subjects are expected at each center, data from all centers will be 
pooled (i.e., no center effect will be included in statistical models). 
6.6  Multiple Comparisons/Multiplicity 
As there will be no statistical testing given the small sample size, no adjustment for multiple 
comparisons will be made. 
6.7  Active-Control Studies Intended to Show Equivalence 
This study was not an active control study intended to show equivalence. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 13 of 35 
 
Version 2.0 
  
6.8  Examination of Subgroups 
No subgroup analyses will be conducted give the small number of patients in this study. 
6  
ANALYSIS POPULATIONS AND VISITS 
7.1  Efficacy/PD Analysis Populations 
The intention-to-treat (ITT) population will consist of all subjects who are enrolled and 
eligible to enter Stage 2.  The ITT population will be the primary analysis population 
analyzed for efficacy/PD endpoints.  
The Per Protocol population will consist of all subjects in the ITT population who completed 
Stage 2 without any major protocol violations that could potentially affect the efficacy 
conclusions of the study. The major protocol violations will be determined with the following 
conditions, but not limited to:  
1. Subjects with no detectable TED level in blood as part of PK assessment or no PK 
assessment.  
2. Absence of Week 20 and Week 24 visits 
3. Non-compliance to study medication for the treatment group 
Compliance is defined in Section 9. 
4. Discrepancies between planned and actual treatment 
The Per Protocol (PP) population will be the secondary analysis population analyzed for 
efficacy endpoints.  
7.2  Safety Analysis Population 
The Safety Population will consist of all subjects in the ITT population who receive at least 
one dose of study medication. All safety analyses will be conducted on this population, 
unless otherwise specified.   
All data will be included in the listings. 
7.3  PK Analysis Population (Stage 2 Only) 
The PK Analysis Population is defined as all subjects, at Stage 2, in the Safety Analysis 
Population for whom the primary PK data are considered sufficient and interpretable. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 14 of 35 
 
Version 2.0 
  
7.4    Windowing Visits 
Although there is a visit window from 2 to 7 days around the expected visit date, nominal 
visits will be used for the per-visit analyses.  Therefore, no windowing of visits by actual 
study day will be done for data obtained at the scheduled visits. For subjects who withdraw 
from the study pre-maturely, if the early termination visit falls into the window of a 
scheduled visit as defined in the protocol, the early termination visit is also summarized for 
that scheduled visit, unless the scheduled visit already took place. 
7  
STUDY SUBJECTS 
8.1  Subjects Screened and Enrolled 
The number of subjects enrolled, and the number of subjects treated will be presented. 
8.2    Study Analysis Populations 
The number and percent of subjects in each study analysis population (i.e., ITT and Safety) 
will be presented. 
8.3  Protocol Deviations 
A listing of subjects with protocol deviations will be presented in the data listings. The 
number and percent of subjects with protocol deviations will be summarized.  The unique 
type of protocol deviations will be summarized for the ITT population. 
8.4  Disposition of Subjects 
For the ITT and Safety populations, study enrollment and completion will be summarized by 
the number and percent of subjects who complete Stages 2, Stage 3, Stage 3 V7and Stage 4. 
The number and percent of subjects by the reason for discontinuing each stage early will also 
be presented. 
8  
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
9.1  Analysis of Demographic and Other Baseline Characteristics 
The baseline and demographic characteristics will be summarized with descriptive statistics 
defined in Section 6.1 for the ITT and Safety Population. Demographic and baseline 
characteristics to be presented include: 
• age (at informed consent date) in years, both as a continuous parameter and by 
categories of <45, 45-<65, and ≥65. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 15 of 35 
 
Version 2.0 
  
• gender 
• race 
• ethnicity 
• height (cm) at the Baseline visit 
• weight (kg) at the Baseline visit 
• body mass index (BMI) (kg/m2) at the Baseline visit 
BMI is calculated as body weight (kg)/body height2 (m). 
The following Short Bowel Syndrome History information collected at the Screening visit 
(i.e., Visit 1.0) will be summarized with descriptive statistics defined in Section 6.1 for the 
ITT and Safety Populations: 
• Duration of SBS (years) 
• reason for major intestinal resection (Crohn’s disease, vascular disease, injury, 
volvulus,  cancer, and other) 
• stoma (Y/N),  stoma type (jejunostomy, ileostromy, colostomy, other) 
• Remaining colon (Y/N), estimated percent colon remaining, and colon in continuity 
(Y/N) 
• Colonoscopy in the last 6 months (Y/N/NA) 
• Total estimated remaining small intestinal length (cm) and category (< 25 cm, 
≥ 25 cm; < 40 cm, ≥ 40 cm; < 60 cm, ≥ 60 cm) 
• Distal/terminal ileum (Y/N) and ileocecal valve (Y/N) 
• Method to determine remaining anatomy length (surgery, radiology, other) 
Duration of SBS will be calculated as (Date of Informed Consent Form Signed – Date of 
Diagnosis of SBS +1)/365.25. 
The following Parenteral Nutrition History information collected at the Screening visit (i.e., 
Visit 1.0) will be summarized with descriptive statistics defined in Section 6.1 for the ITT 
and Safety Populations: 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 16 of 35 
 
Version 2.0 
  
• years since start of PN dependency 
• prescribed weekly PN/IV volume 
• actual weekly PN/IV volume 
• prescribed weekly PN calorie 
• actual weekly PN calorie 
• prescribed weekly number of days of PN/IV 
• actual weekly number of days of PN/IV 
The following Crohn’s Disease Evaluation information collected at the Screening visit (i.e., 
Visit 1.0) will be summarized with descriptive statistics defined in Section 6.1  for the ITT 
and Safety Population: 
• Has a medical history of Crohn’s disease (Y/N), and current clinical status of Crohn’s 
disease (Active, Inactive)  
The following Gastrointestinal–specific Testing information collected during the stabilization 
period will be summarized with descriptive statistics defined in Section 6.1  for the ITT and 
Safety Population: 
• For subjects with Crohn’s disease, upper gastrointestinal contrast series with small 
bowel follow-through (normal, abnormal not clinically significant, abnormal 
clinically significant) 
• abdominal ultrasound (normal, abnormal not clinically significant, abnormal 
clinically significant) 
• colonoscopy (normal, abnormal not clinically significant, abnormal clinically 
significant) 
• sigmoidoscopy (normal, abnormal not clinically significant, abnormal clinically 
significant) 
Colonoscopy and sigmoidoscopy will also be collected at the end of Stage 2 and Stage 3. 
Partial dates for the start date of PN dependency and date of last surgical resection will use 
the first day of the month if only the day is missing.  If both the day and month are missing, 
the first of January will be used. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 17 of 35 
 
Version 2.0 
  
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities.  Investigator verbatim as well as preferred terms and body systems will be 
included in the listings. The medical history will be summarized by system organ class 
(SOC) and preferred term (PT) within system organ class for the Safety Population, with 
SOC sorted alphabetically and PT within SOC by descending incidence. 
9  
MEASUREMENTS OF TREATMENT COMPLIANCE 
Percent compliance will be calculated as 100 times the doses administered divided by the 
number of days on treatment. Doses administered will be calculated as the total number of 
vials dispensed minus the total number of vials returned unused during the study period. 
Number of days on treatment is calculated as (last dose date – first dose date +1). Drug 
accountability information, first dose date, last dose date, and study medication interruptions 
are reported in the eCRF. Subjects will be considered compliant overall for study medication 
if the calculated compliance is > =80%.  Overall treatment compliance will be presented for 
both percent compliance calculations using descriptive statistics and the number and 
percentage of subjects who are >= 80% compliant for both the ITT and Safety Populations. 
Treatment compliance by visit will not be calculated.  Compliance for Stage 2 Only will also 
be calculated.  
Information about interruptions of study medication (start date of interruption, date study 
medication resumed, and reason for interruption) is included in data listings.  
10  
EFFICACY/PHARMACODYNAMIC EVALUATION 
11.1 Analysis of Efficacy and Pharmacodynamic Variables 
All efficacy/pharmacodynamic analyses will be conducted on the ITT and PP populations. 
Analyses on weekly PN/IV support are based on two data sources: the subject diary data(also 
referred to as actual data) and the investigator prescribed data. 
 Investigator prescribed data is captured in the PN history and adjustments eCRFs. The actual 
weekly PN volume will be calculated based on the daily volumes recorded in subjects’ 
diaries within 14 days prior to each scheduled visit. The calculation will follow the formula 
below. 
Weekly value = (sum of daily values in the diary/number of days with values) *7  
Missing daily PN volumes will not be imputed. If there are more than 5 days of missing diary 
data within an interval, the interval will be classified as missing actual volume information. 
An exception to this rule is the Baseline visit, which case traced back beyond 14 days prior to 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 18 of 35 
 
Version 2.0 
  
first dose until 9 data points were obtained. Data will be summarized at all scheduled visits.  
An End of Treatment (EOT) time point will also be added. Therefore, 
• PN/IV volume/ calories and days per week of PN/IV support will be summarized at 
Baseline, Stage 2 Weeks 2, 4, 8, 12, 16, 20, 24, and nominal visits in Stage 3 and 
Stage 4 will be summarized.  
• Plasma citrulline will be summarized at Baseline, Stage 2 Weeks 4, 8, 16, 24, and 
nominal visits in Stage 3 and Stage 4 will be summarized. 
Data collected at unscheduled time points will be included in the listings but will not be 
summarized at those unscheduled time points. 
Change in weekly PN/IV volume from baseline  
The absolute and percent change in weekly PN/IV volume from baseline to each scheduled 
visit, as well as at EOT, will be presented using descriptive statistics defined in Section 6.1.  
The 95% confidence intervals will be presented for Week 24 and End of Stage 2.  
Response to Teduglutide 
The number and percentage of subjects who demonstrate a response at Week 20 and again at 
Week 24 will be presented.  A response is defined as the achievement of at least a 20%  
reduction from baseline (Visit 2) in weekly PN/I.V. volume. 
Binary response to Teduglutide 
The number and percentage of subjects who demonstrate a response at each visit will be 
presented.  A response is defined as the achievement of at least a 20% reduction from 
baseline (Visit 2) in weekly PN/I.V. volume. 
 
Change in days per week of PN/IV support from baseline 
The absolute change in days per week of PN/IV support from baseline to each scheduled 
visit, as well as at EOT, will be presented using descriptive statistics defined in Section 6.1. 
Changes in plasma citrulline from baseline 
The absolute and percent change in plasma citrulline from baseline to each scheduled visit, as 
well as at EOT, will be presented using descriptive statistics defined in Section 6.1. 
Number of subjects who are able to completely wean off PN/IV support 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 19 of 35 
 
Version 2.0 
  
A subject will be considered to have achieved independence from PN/IV (completely weaned 
off PN) if the investigator prescribes no PN and there is no use of PN recorded in the subject 
diary at the last dosing visit.  
The number and percentage of subjects who completely wean off PN/IV support up to Week 
24 in Stage 2 will be presented.  Also, similar analysis will be done for those completely 
wean off PN/IV support at end of Stage 3 and end of study.  
11  
PHARMACOKINETIC EVALUATION  
Details of pharmacokinetic evaluation are included in the Pharmacokinetic Analysis Plan. 
12  
SAFETY EVALUATION 
All safety evaluations will be conducted on the Safety population at the following time 
points. 
• Concomitant medication will be summarized for the study period for all enrolled 
subjects. 
• AEs will be summarized for the study period for all enrolled subjects. 
• Vital signs will be summarized at Baseline, Stage 2 Weeks 2, 4, 8, 12, 16, 20, 24, and 
nominal visits in Stage 3 and Stage 4 will be summarized. 
• Electrocardiograms will be summarized at Baseline, Stage 2 Weeks 4, 24, and 
nominal visits in Stage 3 and Stage 4 will be summarized.  
• Lab tests will be summarized at Baseline, Stage 2 Weeks 2, 4, 8, 12, 16, 20, 24, and 
nominal visits in Stage 3 and Stage 4 will be summarized. 
• Antibodies to teduglutide and ECP will be summarized at Baseline, Stage 2 Weeks 
12, 24, and nominal visits in Stage 3 and Stage 4 will be summarized. 
• 48-hour oral fluid intake and 48-hour urine output will be summarized at Baseline, 
Stage 2 Weeks 2, 4, 8, 12, 16, 20, 24, and nominal visits in Stage 3 and Stage 4 will 
be summarized. 
• Body weight and BMI will be summarized at Baseline, Stage 2 Weeks 2, 4, 8, 12, 16, 
20, 24, and nominal visits in Stage 3 and Stage 4 will be summarized. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 20 of 35 
 
Version 2.0 
  
Complete dates will be imputed from partial dates of adverse events and medications solely 
for the purpose of defining treatment emergence for adverse events and prior/concomitant 
status for medications.  Dates will be defined using the hierarchy of derivations below. 
Adverse event or medication start date (references to month are the month of the start date): 
1. If year and month are known, and it is the month and year of the first dose date, use 
the first dose date. 
2. If year and month are known, and it is the month and year of the informed consent, 
use the informed consent date. 
3. If year and month are known, and the month is not the month and year of the first 
dose or informed consent, use the first day of the month. 
4. If only year is known, and it is previous to the year of the informed consent, use June 
30th of that year. 
5. If only year is known, and it is the year of the informed consent, use the informed 
consent date. 
6. Should any of the previous start dates created be after a complete stop date provided, 
use the stop date instead of the date that would otherwise be created. 
7. Otherwise, if start date is unknown leave as missing. 
 Medication stop date (references to month are the month of the stop date): 
1. If year and month are known and study medication stopped during that month and 
year, use the stop date of study medication.  
2. If year and month are known and informed consent was provided during that month 
and year, use the date of informed consent.  
3. If year and month are known and study medication stopped after the date of informed 
consent and not in the month that medication stopped, use the last day of the month. 
4. If year and month are known and are prior to the month of informed consent, use the 
first day of the month.  
5. If only year is known and study medication stopped during that year, use the stop 
date of study medication. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 21 of 35 
 
Version 2.0 
  
6. If only year is known and study medication stopped after that year, use December 
31st of that year. 
7. If only year is known and study medication stopped prior to that year, use the first 
day of the year. 
8. Should any of the previous stop dates created be before a start date, either a complete 
date or an imputed one, use the (imputed) start date instead of the date that would 
otherwise be created. 
9. Otherwise, if stop date is unknown leave as missing. 
13.1 Extent of Exposure 
The extent of exposure is defined as the number of days on treatment, calculated as: 
(date of last dose - date of first dose) + 1. 
The first dose date, last dose date, and interruptions of study medication will be based on the 
eCRF. The extent of exposure, the number of days that the dose was administered will be 
summarized. The number and percentages of subject will be tabulated for extent of exposure 
categorized into months (<6 months, 6 – <12 months, 12 – <24 months, 24 – <30 months, 
>=30 months). Exposure summaries will be presented for the ITT and Safety Population. 
13.2 Adverse Events 
Adverse events will be summarized in three categories:  1) Overall TEAEs that happened in 
the study, 2) TEAEs that happened in Stage 2, and 3) TEAEs that happened in Stage 3 and 4.  
AEs will be coded using the MedDRA.  Investigator verbatim as well as preferred terms and 
body systems will be included in the listings, and the corresponding list of body systems, 
preferred terms and the verbatim terms that code to each preferred term will be presented as a 
preface to the listings of the AEs. 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens, 
or intensity increases after receiving the study medication.  AEs with an unknown date of 
onset and a stop date after the start of the study period or unknown will be included as 
treatment emergent AEs.  Any AE with a start date equal to the date of first dose, where the 
time of the AE can’t definitively place the start of the AE prior to the first dose, will be 
considered treatment emergent. If any AE records contain only partial dates, these will be 
handled by imputation, as described in Section 6.3.  AEs which are not treatment emergent 
will be flagged in listings. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 22 of 35 
 
Version 2.0 
  
AEs will be summarized overall using descriptive statistics (e.g., number and percent of 
subjects).  The number of events will also be presented except for summaries by highest 
category.  Categories summarized will include any TEAEs, severity of TEAEs (any and 
highest category), investigator assessment of relationship of TEAEs to study treatment, 
treatment emergent serious AEs (TESAEs), severity of TESAEs, investigator assessment of 
relationship of TESAEs to study treatment, TEAEs leading to death, and TEAEs leading to 
discontinuation. 
Treatment emergent AEs will be summarized using number and percentage of subjects.  
Subject incidence for AEs within each SOC and PT will be presented, unless otherwise 
specified.  TEAEs will be summarized by Severity. The number of events will also be 
summarized except for summaries by highest category.  TEAEs will be summarized by 
relationship to the drug, whether it is related or not related.   TESAEs will be summarized.  
TESAE will also be summarized based on Severity as well as Relationship.  Presentation by 
SOC and PT will present SOC sorted alphabetically and PT within SOC by descending 
incidence. 
Summaries of TEAEs, related TEAEs, and TESAEs will also be presented by PT.  These 
presentations will be sorted by descending incidence. 
Listings will be provided for serious adverse events (SAEs), AEs leading to death, and AEs 
leading to discontinuation of study drug.  The listings will be sorted by subject identifier and 
will include gender, age, SOC, PT, reported term, start date/time, end date/time, frequency, 
severity, relationship, action taken, and outcome. 
Pre-Treatment AEs will be summarized. These AEs will be summarized using number and 
percentage of subjects. Subject incidence for AEs within each SOC and PT will be presented. 
The number of events will also be summarized. Presentation by SOC and PT will present 
SOC sorted alphabetically and PT within SOC by descending incidence. 
TEAEs will summarized by time to onset (<6 months, 6 – <12 months, 12 – <24 months, 24 
– <30 months, >=30 months). These AEs will be summarized using number and percentage 
of subjects. Subject incidence for AEs within each SOC and PT will be presented. The 
number of events will also be summarized. Presentation by SOC and PT will present SOC 
sorted alphabetically and PT within SOC by descending incidence. 
One of the benefits of Teduglutide’s ability to reduce PN assumption is to reduce or 
eliminate the risk of systemic catheter-related infections in SBS patients who are PN 
dependent. Adverse events that are considered to be central line systemic infections include 
central line infection, catheter related infection, catheter sepsis, catheter bacteraemia, 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 23 of 35 
 
Version 2.0 
  
bacteraemia, and blood culture positive. These TEAEs will be presented by PT, sorted by 
descending incidence. 
13.3 Clinical Laboratory Evaluation 
Laboratory parameters will be collected and processed via a central laboratory, SRL, and 
presented in standard international (SI) units.  Clinical laboratory evaluations include the 
following: 
• Chemistry 
o Alanine Aminotransferase 
o Albumin 
o Alkaline Phosphatase 
o Amylase 
o Aspartate Aminotransferase 
o Total Bilirubin 
o Direct Bilirubin 
o Indirect Bilirubin 
o Blood Urea Nitrogen 
o C Reactive Protein 
o Calcium 
o Chloride 
o Total Cholesterol 
o Creatinine  
o Creatinine Clearance 
o Gamma Glutamyl Transferase 
o Glucose 
o Lipase 
o Magnesium 
o Phosphate 
o Potassium 
o Sodium 
o Triglycerides 
o Uric Acid 
• Hematology 
o Erythrocytes 
o Hematocrit 
o Hemoglobin 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 24 of 35 
 
Version 2.0 
  
o Leukocytes 
o Platelets 
• Urinalysis 
o Urine Blood 
o Urine Glucose 
o Urine Leukocytes 
o Urine Microscopic  
o pH 
o Urine Osmolality 
o Urine Protein 
o Urine Sodium 
Quantitative results will be summarized for hematology, serum chemistry, and selected 
urinalysis parameters at each visit collected and at endpoint.  Both actual values and change 
from baseline will be summarized with descriptive statistics defined in Section 6.1.  
Additionally, shift tables will be presented for parameters provided by the central laboratory, 
summarizing cross tabulations of low, normal, and high based on the parameter normal 
range, from baseline to Week 24, End of Stage 3 and End of Stage 4.  Percentages for shift 
tables will be based on the number of subjects with a value at baseline and at least one post-
baseline visit. 
Markedly abnormal laboratory values are defined in Table 3. These criteria are based on lab 
normal ranges and discussions with the experts. The number and percentage of subjects with 
post-baseline results qualifying as markedly abnormal as defined in this table will be 
summarized by parameter.  A listing will present all values for a subject and laboratory 
parameter if at least one post-baseline value for that subject and parameter is markedly 
abnormal.   
Table 3 Markedly Abnormal Laboratory Criteria  
Lab parameter 
Unit 
Lower Limit 
Upper Limit 
Chemistry 
Albumin 
g/L 
<=20 
>=90 
Alkaline Phosphatase 
U/L 
NA 
>2*ULN 
ALT 
U/L 
NA 
>3*ULN 
Amylase 
U/L 
<=15 
>=350 
AST 
U/L 
NA 
>3*ULN 
Bilirubin (total) 
µmol/L 
NA 
>2*ULN 
BUN 
mmol/L 
NA 
>=10.7 
Calcium (total) 
mmol/L 
<=2.1 
>=3.0 
Chloride 
mmol/L 
<=80 
>=125 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 25 of 35 
 
Version 2.0 
  
Cholesterol (total) 
mmol/L 
NA 
>=12.9 
Creatinine 
µmol/L 
NA 
>=177 
C Reactive Protein 
mg/L 
NA 
>21 
Glucose 
mmol/L 
<=1.7 
>=13.9 
Gamma glutamyl 
transferase 
U/L 
NA 
>=100 
Lipase 
U/L 
NA 
>3*ULN 
Magnesium 
mmol/L 
<LLN 
>ULN 
Phosphate 
mmol/L 
NA 
>=2.0 
Potassium 
mmol/L 
<=2.5 
>=6.5 
Sodium 
mmol/L 
<=120 
>=165 
Triglycerides 
mmol/L 
NA 
>=5.6 
Uric acid 
µmol/L 
NA 
>=624 (males) 
>=505 (females) 
Hematology 
Hematocrit 
L/L 
<=0.37 (males) 
<=0.32 (females) 
>0.54 (males) 
NA (females) 
Hemoglobin 
g/L 
<=115 (males) 
<=95 (females) 
NA 
Platelets 
109/L 
<=75 
>=700 
 
Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis) by subject, visit, and parameter.  Laboratory values outside of the 
normal range will be flagged.  Categorical urinalysis findings and urine pregnancy results 
will be presented in appendix data listings only. 
13.4 Vital Signs 
Descriptive statistics (e.g., mean, standard deviation, median, minimum and maximum 
values, the number and percent of subjects in specified categories) will be used to summarize 
the vital signs (i.e., sitting systolic blood pressure, sitting diastolic blood pressure, seated 
pulse rates, body temperature,  weight, height, and BMI) by visit and at EOT.  Both actual 
value and change from baseline will be summarized with descriptive statistics defined in 
Section 6.1.   
13.5 ECG Variables 
The number and percentage of subjects with each type of ECG finding (Normal/Abnormal, 
Not Clinically Significant/Abnormal, Clinically Significant) will be presented at Baseline, 
Week 4, 24, and nominal visits in Stage 3 and Stage 4 will be summarized. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 26 of 35 
 
Version 2.0 
  
13.6 Physical Examination 
Physical examination results will be presented in appendix data listings only.  Any clinically 
significant findings for physical examinations were to be recorded as medical history at 
screening or as adverse events for all other visits. 
13.7 Antibodies to Teduglutide and Escherichia coli Protein (ECP) 
A summary table will provide the number of subjects with a sample analyzed for Baseline, 
Weeks 12, 24, and nominal visits in Stage 3 and Stage 4 will be summarized.  The summary 
table will also provide the number of subjects with an antibody finding at each of those visits.   
13.8  Prior and Concomitant Medications 
Prior and concomitant medications will be coded to indication-specific ATC (Anatomic 
Therapeutic Chemical classification) and preferred name using the World Health 
Organization Drug Dictionary.  Investigator verbatim as well as coded terms will be included 
in the listings. 
Prior medications are defined as medications taken prior to the first dose of study medication.  
Concomitant medications are defined as medications with onset dates on or after the first 
dose of study medication, medications with onset dates prior to first dose of study medication 
without a stop date, or medications with a stop date after first dose of study medication.  The 
subject’s PN and any components of their PN should not be recorded as a prior or 
concomitant medication.  Partial date imputation for medications is described in Section 6.3.  
Prior and concomitant medication use will be summarized by preferred name using the 
number and percentage of subjects.  Medications will be sorted alphabetically by ATC and 
preferred name within ATC.  Subjects with multiple occurrences of a medication in ATC and 
preferred name will only be counted once within each ATC and preferred name.  Since 
medications are coded to ATC by indication, preferred names may appear under multiple 
ATCs. 
A listing of all medications, both prior and concomitant, will be presented.  Any 
abbreviations and codes will be clearly explained on each page of the listing.  The listing will 
be sorted by subject identifier and will include fourth level ATC code, reported name, dose, 
route of administration, dosing frequency, start date, end date, indication, and period of 
medication (prior only, concomitant only, prior and concomitant). 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 27 of 35 
 
Version 2.0 
  
13 
 CHANGES TO THE STATISTICAL METHODOLOGY PRESENTED IN 
THE PROTOCOL 
There are some changes in SAP plan from the protocol as follows;  
• PN/IV volume/ calories based on Investigator Prescribed Data will be summarized. 
• Binary response to Teduglutide at each visit will be summarized. 
• The comparisons with the results of Phase 3 Study CL0600 020, defined in the 
protocol, will not be performed, and thus will not be included in the clinical study 
report.  
14  
GENERAL PROGRAMMING INFORMATION 
15.1 General 
All programmed table, figure and listing outputs, unless specified otherwise, will be 
generated using the SAS version 9.2 or later.  The programmed outputs will be similar to the 
format/appearance of the table and listing shells.  However, space/formatting limitations may 
dictate changes in the programmed output.  The footnotes specified in the table and listing 
shells may be changed as necessary for clarifying table entries or the explanation of 
algorithms or methods used for producing the entries.  Significant changes in footnotes will 
be discussed prior to their implementation. 
15.2 Format of Tables/Listings 
Tables and listings should be produced in landscape mode and centered horizontally.  
Required margins are 1 inch for the top, left, right and bottom margins.  All output should 
have a 3-line header at the upper left margin: 
Shire 
TED-C14-004 
Confidential 
All output should have a 1-linefooter with the SAS program name, including the path, and 
the date and time the output was produced at the lower left margin of the footer.  Tables will 
have the report listings for the data analyses presented in the table identified at the lower left 
margin, and listings will have the source eCRF identified. 
Tables and listings should be internally paginated in relation to the total length for that table 
or listing (i.e., Page n of N, where n is the page number within the table or listing and N is 
the total number of pages for that table or listing). 
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines. 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 28 of 35 
 
Version 2.0 
  
A number should identify each table/listing, and the table designation (e.g., Table 1) should 
be centered above the title.  A decimal system (e.g., x, x.y, x.y.z) should be used to identify 
tables/listings with related contents.  The title should be centered and in mixed-case 
characters.  The title and table/listing designation should be single-spaced but are separated 
from the content of the table/listing by a space and a solid underline.  The study population 
and/or subgroup (e.g., ITT Population) should be identified on the line immediately 
following the title. 
Column headings should be in initial upper-case characters.  For numeric variables, the unit 
should be included in the column heading when appropriate. 
Footnotes should be single spaced, but separated by an underline and a space from the text of 
the table/listing.  The notes should be aligned vertically by the left vertical border of the 
table/listing.  Numeric references, which can be confused with data, should not be used.  
Rather asterisks and other non-numeric symbols should be used to refer to footnotes. 
The dictionary (e.g., MedDRA, WHO-DRUG) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary.   
For summarizations of categorical data, an Unknown or Missing category should be added to 
any variable for which information is not available for all subjects.  However, only the 
number of unknown or missing subjects will be presented, and percent will be based on non-
missing data. 
Individual data listings will be sorted and presented by subject number and visit date. 
15.3 Data Formats 
Unless otherwise specified, means and medians will be rounded and presented to 1 decimal 
place more than the raw data and standard deviations to 2 decimal places more than the raw 
data.  Minimum and maximum values will be presented to the same number of decimal 
places as the raw data. 
Data in columns will be formatted as follows: 
• Alphanumeric values will be center-justified (in mixed upper and lower-case) 
• Numerical data will be decimal aligned. 
• Fractional data should be presented with the zero to the left of the decimal point 
(e.g., 0.54). 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 29 of 35 
 
Version 2.0 
  
Unless otherwise specified, percentages should be presented to one decimal place.  Less than 
signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be presented as 
< 0.1%, not 0.0%). 
Dates will be presented in a DDMONYY format.  Dates with partial missing data will be 
presented with a dash (i.e., ‘-‘) for the missing data (e.g., --JAN05). 
15  
LISTINGS OF TABLE, FIGURE AND DATA LISTINGS 
16.1 List of Tables 
Table 14.1.1 
Study Analysis Populations 
All Enrolled Subjects 
Table 14.1.1.1 
Protocol Deviations 
Intention-to-Treat Population 
Table 14.1.2.1 
Subject Disposition 
Intention-to-Treat Population 
Table 14.1.2.2 
Subject Disposition 
Safety Population 
Table 14.1.3.1 
Demographics and Baseline Characteristics 
Intention-to-Treat Population 
Table 14.1.3.2 
Demographics and Baseline Characteristics 
Safety Population 
Table 14.1.4.1 
Short Bowel Syndrome History 
Intention-to-Treat Population 
Table 14.1.4.2 
Short Bowel Syndrome History 
Safety Population 
Table 14.1.5.1 
Parenteral Nutrition History 
Intention-to-Treat Population 
Table 14.1.5.2 
Parenteral Nutrition History 
Safety Population 
Table 14.1.6.1 
Crohn`s Disease Evaluation 
Intention-to-Treat Population 
Table 14.1.6.2 
Crohn`s Disease Evaluation 
Safety Population 
Table 14.1.7.1 
Gastrointestinal-specific Testing 
Intention-to-Treat Population 
Table 14.1.7.2 
Gastrointestinal-specific Testing 
Safety Population 
Table 14.1.8 
Medical and Surgical History 
Safety Population 
Table 14.1.9.1 
Prior Medications 
Safety Population 
Table 14.1.9.2 
Concomitant Medications 
Safety Population 
Table 14.1.10.1 
Study Medication Compliance 
Intention-to-Treat Population 
Table 14.1.10.1.1 
Study Medication Compliance - Stage 2 Only 
Intention-to-Treat Population 
Table 14.1.10.2 
Study Medication Compliance 
Safety Population 
Table 14.2.1.1 
Summary of Response to Teduglutide Based on Subject 
Diary Data 
Intention-to-Treat Population 
Table 14.2.1.2 
Summary of Response to Teduglutide Based on Subject 
Diary Data 
Per-Protocol Population 
Table 14.2.1.3 
Summary of Response to Teduglutide Based on 
Investigator Prescribed Data 
Intention-to-Treat Population 
Table 14.2.1.4 
Summary of Response to Teduglutide Based on 
Investigator Prescribed Data 
Per-Protocol Population 
Table 14.2.2.1 
Binary Response Status by Visit Based on Subject 
Diary Data 
Intention-to-Treat Population 
Table 14.2.2.2 
Binary Response Status by Visit Based on Subject 
Diary Data 
Per-Protocol Population 
Table 14.2.2.3 
Binary Response Status by Visit Based on Investigator 
Prescribed Data 
Intention-to-Treat Population 
Table 14.2.2.4 
Binary Response Status by Visit Based on Investigator 
Prescribed Data 
Per-Protocol Population 
Table 14.2.3.1 
Change and Percent Change in PN Volume from 
Intention-to-Treat Population 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 30 of 35 
 
Version 2.0 
  
Baseline by Visit Based on Subject Diary Data 
Table 14.2.3.2 
Change and Percent Change in PN Volume from 
Baseline by Visit Based on Subject Diary Data 
Per-Protocol Population 
Table 14.2.3.3 
Change and Percent Change in PN Volume from 
Baseline by Visit Based on Investigator Prescribed Data 
Intention-to-Treat Population 
Table 14.2.3.4 
Change and Percent Change in PN Volume from 
Baseline by Visit Based on Investigator Prescribed Data 
Per-Protocol Population 
Table 14.2.4.1 
Change and Percent Change in Number of Days of PN 
Usage from Baseline by Visit Based on Investigator 
Prescribed Data 
Intention-to-Treat Population 
Table 14.2.4.2 
Change and Percent Change in Number of Days of PN 
Usage from Baseline by Visit Based on Investigator 
Prescribed Data 
Per-Protocol Population 
Table 14.2.5 
Number (%) of Subjects Who Stop PN Usage Based on 
Prescribed and Subject Diary Data 
Intention-to-Treat Population 
Table 14.2.6 
Change and Percent Change in PN Kilocalories from 
Baseline by Visit 
Intention-to-Treat Population 
Table 14.2.7 
Change and Percent Change in Citrulline from Baseline 
by Visit 
Intention-to-Treat Population 
Table 14.3.1.1 
Extent of Exposure 
Intention-to-Treat Population 
Table 14.3.1.2 
Extent of Exposure 
Safety Population 
Table 14.3.2.1 
Overall Summary of Treatment Emergent Adverse 
Events 
Safety Population 
Table 14.3.2.1.1 
Overall Summary of Treatment Emergent Adverse 
Events - Stage 2 Only  
Safety Population 
Table 14.3.2.1.2  
Overall Summary of Treatment Emergent Adverse 
Events - Stage 3 and 4 Only  
Safety Population 
Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.2.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term - Stage 2 Only 
Safety Population 
Table 14.3.2.2.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term - Stage 3 and 4 
Only 
Safety Population 
Table 14.3.2.2.3 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term - Stage 3 Only  
Safety Population 
Table 14.3.2.2.4 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term - Stage 4 Only 
Safety Population 
Table 14.3.2.3 
Summary of Treatment Emergent Adverse Events by 
Preferred Term 
Safety Population 
Table 14.3.2.3.1 
Summary of Treatment Emergent Adverse Events by 
Preferred Term - Stage 2 Only 
Safety Population 
Table 14.3.2.3.2 
Summary of Treatment Emergent Adverse Events by 
Preferred Term - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.4 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity 
Safety Population 
Table 14.3.2.4.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity - 
Stage 2 Only 
Safety Population 
Table 14.3.2.4.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity - 
Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.5 
Summary of Related Treatment Emergent Adverse 
Safety Population 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 31 of 35 
 
Version 2.0 
  
Events by System Organ Class and Preferred Term 
Table 14.3.2.5.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship - 
Stage 2 Only 
Safety Population 
Table 14.3.2.5.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship - 
Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.5.3 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship - 
Stage 3 Only 
Safety Population 
Table 14.3.2.5.4 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship - 
Stage 4 Only 
Safety Population 
Table 14.3.2.6 
Summary of Related Treatment Emergent Adverse 
Events by Preferred Term 
Safety Population 
Table 14.3.2.6.1 
Summary of Treatment Emergent Adverse Events by 
Preferred Term and Relationship - Stage 2 Only 
Safety Population 
Table 14.3.2.6.2 
Summary of Treatment Emergent Adverse Events by 
Preferred Term and Relationship - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.7 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.7.1 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class and Preferred Term - 
Stage 2 Only 
Safety Population 
Table 14.3.2.7.2 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class and Preferred Term - 
Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.8  
Summary of Treatment Emergent Serious Adverse 
Events by Preferred Term 
Safety Population 
Table 14.3.2.8.1 
Summary of Treatment Emergent Serious Adverse 
Events by Preferred Term - Stage 2 Only 
Safety Population 
Table 14.3.2.8.2 
Summary of Treatment Emergent Serious Adverse 
Events by Preferred Term - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.9 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class, Preferred Term, and 
Severity 
Safety Population 
Table 14.3.2.9.1 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class, Preferred Term, and 
Severity - Stage 2 Only 
Safety Population 
Table 14.3.2.9.2 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class, Preferred Term, and 
Severity - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.10 
Summary of Related Treatment Emergent Serious 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
Table 14.3.2.10.1 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class, Preferred Term, and 
Relationship - Stage 2 Only 
Safety Population 
Table 14.3.2.10.2 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class, Preferred Term, and 
Relationship - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.11 
Details of Serious Adverse Events 
Safety Population 
Table 14.3.2.11.1 
Details of Serious Adverse Events - Stage 2 Only 
Safety Population 
Table 14.3.2.11.2 
Details of Serious Adverse Events - Stage 3 and 4 Only 
Safety Population 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 32 of 35 
 
Version 2.0 
  
Table 14.3.2.12 
Summary of Treatment Emergent Adverse Events 
Leading to Discontinuation by System Organ Class and 
Preferred Term 
Safety Population 
Table 14.3.2.12.1 
Summary of Treatment Emergent Adverse Events 
Leading to Discontinuation by System Organ Class and 
Preferred Term - Stage 2 Only 
Safety Population 
Table 14.3.2.12.2 
Summary of Treatment Emergent Adverse Events 
Leading to Discontinuation by System Organ Class and 
Preferred Term - Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.13 
Details of Adverse Events Leading to Discontinuation 
Safety Population 
Table 14.3.2.13.1 
Details of Adverse Events Leading to Discontinuation - 
Stage 2 Only 
Safety Population 
Table 14.3.2.13.2 
Details of Adverse Events Leading to Discontinuation - 
Stage 3 and 4 Only 
Safety Population 
Table 14.3.2.14  
Details of Adverse Events Leading to Death 
Safety Population 
Table 14.3.2.14.1 
Details of Adverse Events Leading to Death - Stage 2 
Safety Population 
Table 14.3.2.14.2 
Details of Adverse Events Leading to Death - Stage 3 
and 4 Only 
Safety Population 
Table 14.3.2.15 
Summary to Treatment Emergent Adverse Events by 
Time to Onset, System Organ Class, and Preferred 
Term 
Safety Population 
Table 14.3.2.16 
Summary of Pre-treatment Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.17 
Summary of Treatment Emergent Central Line 
Systemic Infections by Preferred Term  
Safety Population 
Table 14.3.2.17.1 
Summary of Treatment Emergent Central Line 
Systemic Infections by Preferred Term - Stage 2 Only 
Safety Population 
Table 14.3.2.17.2 
Summary of Treatment Emergent Central Line 
Systemic Infections by Preferred Term - Stage 3 and 4 
Only 
Safety Population 
Table 14.3.3.1 
Summary of Laboratory Values and Change from 
Baseline by Visit - Chemistry 
Safety Population 
Table 14.3.3.2 
Summary of Laboratory Values and Change from 
Baseline by Visit - Hematology 
Safety Population 
Table 14.3.3.3 
Summary of Laboratory Values and Change from 
Baseline by Visit - Urinalysis 
Safety Population 
Table 14.3.3.4 
Summary of Antibody Results by Visit 
Safety Population 
Table 14.3.3.5 
Shift from Baseline to Post-baseline in Clinical 
Laboratory Parameters by Visit - Chemistry  
Safety Population 
Table 14.3.3.6 
Shift from Baseline to Post-baseline in Clinical 
Laboratory Parameters by Visit - Hematology  
Safety Population 
Table 14.3.3.7 
Shift from Baseline to Post-baseline in Clinical 
Laboratory Parameters by Visit - Urinalysis  
Safety Population 
Table 14.3.3.8 
Summary of Post-Baseline Markedly Abnormal 
Laboratory Values – Chemistry  
Safety Population 
Table 14.3.3.9 
Summary of Post-Baseline Markedly Abnormal 
Laboratory Values – Hematology  
Safety Population 
Table 14.3.4.1 
Change and Percent Change in 48-hour Fluid Intake 
from Baseline by Visit  
Safety Population 
Table 14.3.4.2 
Change and Percent Change in 48-hour Urine Output 
from Baseline by Visit  
Safety Population 
Table 14.3.5.1 
Summary of Vital Sign Values and Change from 
Baseline by Visit 
Safety Population 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 33 of 35 
 
Version 2.0 
  
Table 14.3.6.1 
Summary of ECG Findings by Visit 
Safety Population 
 
16.2 List of Figures 
Figure 14.2.1.1.1 
Individual Change in Weekly PN Volume by Visit 
Intention-to-Treat Population 
Figure 14.2.1.1.2 
Mean (SE) Change in Weekly PN Volume by Visit 
Intention-to-Treat Population 
Figure 14.2.1.1.3 
Mean (SE) Change in Weekly PN Volume by Visit – 
Stage 2 Only 
Intention-to-Treat Population 
Figure 14.2.1.2.1  
Individual Percent Change in Weekly PN Volume by 
Visit 
Intention-to-Treat Population 
Figure 14.2.1.2.2 
Mean (SE) Percent Change in Weekly PN Volume by 
Visit 
Intention-to-Treat Population 
Figure 14.2.1.2.3 
Mean (SE) Percent Change in Weekly PN Volume by 
Visit – Stage 2 Only 
Intention-to-Treat Population 
 
16.3 List of Data Listings 
Listing 16.2.1 
Subject Disposition and Completion/Discontinuation 
All Enrolled Subjects 
Listing 16.2.2.1 
Inclusion and Exclusion Criteria Violations  
All Enrolled Subjects 
Listing 16.2.2.2 
Subject Level Protocol Deviations 
All Enrolled Subjects 
Listing 16.2.3 
Demographics  
All Enrolled Subjects 
Listing 16.2.4.1 
SBS History 
All Enrolled Subjects 
Listing 16.2.4.2 
Parenteral Nutrition History 
All Enrolled Subjects 
Listing 16.2.4.3 
Crohn’s Disease Evaluation 
All Enrolled Subjects 
Listing 16.2.4.4 
Medical and Surgical History 
All Enrolled Subjects 
Listing 16.2.4.5 
Prior and Concomitant Medications 
All Enrolled Subjects 
Listing 16.2.4.6 
Study Medication 
All Enrolled Subjects 
Listing 16.2.5.1 
Study Drug Administration 
All Enrolled Subjects 
Listing 16.2.5.2 
Study Drug Accountability 
All Enrolled Subjects 
Listing 16.2.5.3 
Study Drug Interruption 
All Enrolled Subjects 
Listing 16.2.6.1 
PN Usage 
All Enrolled Subjects 
Listing 16.2.6.2 
PN/IV Adjustment 
All Enrolled Subjects 
Listing 16.2.6.3 
48 Hour Parenteral/Enteral Fluid Intake and Urine 
Output 
All Enrolled Subjects 
Listing 16.2.6.4 
PN Nutrition Intake Diary 
All Enrolled Subjects 
Listing 16.2.6.5 
Prescribed and Actual PN Support by Patient and Visit 
All Enrolled Subjects 
Listing 16.2.7.1 
Adverse Events 
All Enrolled Subjects 
Listing 16.2.7.2 
Serious Adverse Events Details 
All Enrolled Subjects 
Listing 16.2.8.1 
Lab Sample Collection 
All Enrolled Subjects 
Listing 16.2.8.2 
Lab Test Results - Chemistry 
All Enrolled Subjects 
Listing 16.2.8.3 
Lab Test Results - Hematology 
All Enrolled Subjects 
Listing 16.2.8.4 
Lab Test Results - Urinalysis 
All Enrolled Subjects 
Listing 16.2.8.5 
Lab Test Results - Citrulline 
All Enrolled Subjects 
Listing 16.2.8.6 
Lab Test Results - Antibody to Teduglutide and ECP 
All Enrolled Subjects 
Listing 16.2.8.7 
Urine Pregnancy Test 
All Enrolled Subjects 
Listing 16.2.8.8 
Diagnostic, Surgical, or Therapeutic Procedures during 
All Enrolled Subjects 


Study TED-C14-004 - Statistical Analysis Plan 
Teduglutide (rNDA origin) for injection  
Page 34 of 35 
 
Version 2.0 
  
the Study 
Listing 16.2.8.9 
Gastrointestinal-specific Testing 
All Enrolled Subjects 
Listing 16.2.8.10 
Physical Examination 
All Enrolled Subjects 
Listing 16.2.8.11 
Vital Signs 
All Enrolled Subjects 
Listing 16.2.8.12 
ECG Tracing Interpretation 
All Enrolled Subjects 
 
16  
TABLE, FIGURE AND DATA LISTING SHELLS 
17.1 Table Shells 
See separate file. 
17.2 Figure Shells 
See separate file. 
17.3 Data Listing Shells 
See separate file.