Clinical trial NCT03596164
Conditions: Short Bowel Syndrome
Sponsor: Takeda
Start date: 2018-07-09; Completion date: 2022-01-13
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this clinical study is to evaluate the long-term safety and efficacy of teduglutide in Japanese participants with PN/IV (parenteral nutrition/intravenous)-dependent SBS (short bowel syndrome) who completed SHP633-306 or who were in the extension phase of the TED-C14-004 (NCT02340819) study.

Detailed description:

Arms: arm 1: Participants will receive Teduglutide 0.05 milligram per kilogram (mg/kg) subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm until Teduglutide is commercially available, the participant's participation in this study is discontinued, or the study is discontinued.
Interventions: intervention 1: Teduglutide intervention 2: Syringe intervention 3: Needle intervention 4: Vial Adapter for Device
Intervention descriptions: intervention 1: Teduglutide 0.05 mg/kg SC injection will be administered once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm. intervention 2: Teduglutide will be administered using syringe. Syringe is approved for use in Japan by PMDA. intervention 3: Teduglutide will be administered using needle. Needle is approved for use in Japan by PMDA. intervention 4: Vial adapter for device is approved for use in Japan by PMDA.

Protocol documents:
SAP_002.pdf: 
 
 
Title: An Open-Label, Extension Study of Teduglutide in Japanese Subjects with Short 
Bowel Syndrome who Completed 24 Weeks of Treatment in SHP633-306 or 
TED-C14-004 
 
NCT Number: NCT03596164 
Statistical analysis plan Approve Date: 16-Feb-2022 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


Takeda  
Page 1 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
STATISTICAL ANALYSIS PLAN 
Teduglutide 
PHASE 3 Extension 
An Open-Label, Extension Study of Teduglutide in Japanese Subjects 
with Short Bowel Syndrome who Completed 24 Weeks of Treatment in 
SHP633-306 or TED-C14-004 
PROTOCOL IDENTIFIER: SHP633-307 
Study Sponsor(s): 
Takeda Human Genetic Therapies, Inc. 300 
Shire Way Lexington, MA 02421 USA 
Author (Company): 
 
Protocol: 
27 SEP 2018, Amendment 1 
SAP Version #:2.0 
SAP Date: 
16Feb2022 
Status: 
 Final 
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Page 3 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
REVISION HISTORY 
Version 
Issue Date 
Summary of Changes 
Draft 1.0 
31May2019 
New Document 
Draft 2.0 
17Jul2019 
-
Definition of prior medication has been
deleted and definition of concomitant
medication has been revised.
-
Summary of extent of exposure categorized
into weeks has been added.
-
Definition and summary of extent of
observation have been added.
-
Summary of adverse event by system organ
class, preferred term and onset time has been
added.
-
Summary of selected efficacy endpoints by
antibody results and visit has been added.
Draft 3.0 
1Oct2019 
-
Definition of Analysis Visit has been added
to be used for summary tables.
-
Definition of total extent of exposure has
been added.
-
Definition of treatment emergent adverse
events (TEAEs) has been updated. The
analysis for related treatment emergent
serious adverse events (TESAEs) has been
added.
Final 1.0 
11Oct2019 
-
Version number
-
Date
Final 2.0 
10Feb2022 
-
Section 5.5: updated the categories for
Extent 
of 
Exposure 
and 
Extent 
of
Observation.
-
Section 6.1: clarified that absolute value in
weekly PN/IV volume is to be analyzed.
-
Section 7.1: added overall summary of
TEAEs leading to study discontinuation.
-
Section 11.3: corrected the corresponding
visits of subject from SHP633-306 from
Analysis Visit Month 27/28/29.
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
ABBREVIATIONS 
AE 
adverse event 
ALT 
Alanine Aminotransferase, equivalent to SGPT 
AST 
Aspartate Aminotransferase, equivalent to SGOT 
AUC 
area under the plasma concentration-time curve 
AUC0–t 
AUC from zero to the last measurable concentration 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
BUN 
Blood Urea Nitrogen 
CL/F 
apparent clearance 
Cmax 
maximum plasma concentration 
CTMS 
clinical trial management system 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EGD 
esophagogastroduodenoscopy 
EOS 
end of study 
ET 
early termination 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
MedDRA Medical Dictionary for Regulatory Activities 
NCA 
non-compartmental analysis 
PK 
pharmacokinetics 
PN/IV 
parenteral nutrition/intravenous 
PT 
preferred terms 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBS 
short bowel syndrome 
SE 
standard error 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
SI 
standard international 
SOC 
system organ class 
t1/2 
terminal-phase half-life 
tmax 
time to Cmax 
TEAE 
treatment emergent adverse event 
TESAE 
treatment emergent serious adverse event 
ULN 
upper limit of normal 
ULQ 
above the upper limit of quantification 
V/F 
apparent volume of distribution 
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Page 9 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
1.
INTRODUCTION
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the
statistical analyses of efficacy, safety and pharmacokinetic (PK) data (descriptive
summaries only) as described in the final study protocol dated 27 Sep 2018 incorporating
most recent amendment 1. Specifications for tables, figures, and listings are contained in
a separate document. Pharmacokinetics analyses (other than descriptive summaries) will
be described in a separate PK SAP.
2.
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS
2.1 
Objectives 
The objectives of this clinical study are to evaluate the long-term safety and efficacy of 
teduglutide in Japanese subjects with parenteral nutrition/intravenous (PN/IV) dependent 
short bowel syndrome (SBS) who completed SHP633-306 or who were in the extension 
phase of the TED-C14-004 study. 
2.2 
Estimands 
Number/percentage of subjects who achieved at least 20% reduction from baseline of the 
core studies (SHP633-306 and TED-C14-004) in weekly PN/IV volume based on diary 
data at end of study (EOS) in Japanese subjects with PN/IV – dependent SBS in the safety 
population. 
Absolute change from baseline of the core studies (SHP633-306 and TED-C14-004) in 
weekly PN/IV volume based on diary data at EOS in Japanese subjects with PN/IV – 
dependent SBS in the safety population. 
Relative change from baseline of the core studies (SHP633-306 and TED-C14-004) in 
weekly PN/IV volume based on diary data at EOS in Japanese subjects with PN/IV – 
dependent SBS in the safety population. 
2.3 
Endpoints 
2.3.1 Efficacy Endpoints 
The following efficacy endpoints will be analyzed at each study visit and at the EOS, 
relative to the baseline of the core studies (SHP633-306 and TED-C14-004): 
Reduction in PN/IV volume of at least 20%
Absolute and relative change in PN/IV volume
Complete weaning off PN/IV
Change in days per week of PN/IV
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Page 10 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Change in plasma citrulline
2.3.2 Safety Endpoints 
The safety endpoints include adverse events (AEs), 12-lead electrocardiogram (ECG), vital 
signs, laboratory safety data, antibodies to teduglutide, and 48-hour urine output, body 
weight, body mass index (BMI) and gastrointestinal-specific tests.   
2.3.3 Pharmacokinetic Endpoints 
The following parameters will be derived as described in a separate PK SAP and reported 
separately:  
Area under the plasma concentration–time curve from zero to the last measurable
concentration (AUC0–t)
Maximum plasma concentration (Cmax)
Time to Cmax (tmax)
terminal-phase half-life (t1/2)
Apparent clearance (CL/F)
Apparent volume of distribution (V/F)
3.
STUDY DESIGN
3.1 
General Description 
This is a long-term extension study to evaluate the safety and efficacy of teduglutide in 
Japanese subjects who completed study SHP633-306 or were in the extension phase of 
TED-C14-004 (core studies). A schematic representation of the study design is presented 
in Figure 1. 
Once informed consent has been obtained, demographics, updates to medical history and 
short bowel syndrome history will be obtained. Teduglutide 0.05 mg/kg will be 
administered once daily until teduglutide is either commercially available, or the subject’s 
participation in this study is discontinued, or the study is discontinued. At each site visit, 
efficacy (adjustments to PN/IV) and safety will be monitored. 
For subjects transitioning from SHP633-306, the SHP633-306 EOS visit assessments will 
be combined with the assessments for the first visit in SHP633-307. Clinic and phone visits 
will then alternate on a monthly basis through Month 24; thereafter, clinic visits will occur 
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Page 11 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
every 3 months. For subjects transitioning from TED-C14-004, the TED-C14-004 EOS 
visit assessments will be combined with the assessments for the first visit in SHP633-307; 
thereafter clinic visits will occur every 3 months. 
Subjects enrolling from TED-C14-004 will have blood samples taken for teduglutide PK 
analysis at predose and at 15, 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at 
the first visit that they enter in this study. Subjects enrolling from SHP633-306 will have 
blood samples taken for teduglutide PK analysis at predose and 1 and 2 hours post dose at 
the first clinic visit in this study. 
Study schedules for subjects enrolling from SHP633-306 and for subjects enrolling from 
TED-C14-004 can be found in the protocol. 
Figure 1: Study Schematic 
Subjects from SHP633-306: Between V1-V25 study visits occur monthly alternating between clinic visits and phone calls  Starting at V25 clinic visits 
occur every 3 months  
Interim safety visits after PN/IV adjustments are not shown  
Subjects from TED-C14-004: End of study assessments for TED-C14-004 are combined with the SHP633-307 assessments at V1  The study physician 
will administer the first dose  The study physician must observe the subject administering the study drug in compliance with the study drug 
administration checklist at least twice before the parent/guardian is allowed to administer the drug without direct observation by the physician  Refer to 
the criteria for self-administration in the Site Training Guide  
3.2 
Randomization 
Not applicable for this single arm study. 
3.3 
Blinding 
Not applicable for this open-label study. 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
3.4 
Sample Size and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this 
is an extension study of the core study SHP633-306 and TED-C14-004. Approximately 5 
subjects who completed study SHP633-306 and 7 subjects in the extension phase of TED-
C14-004 may enroll in this extension study.  
4.
STATISTICAL ANALYSIS SETS
4.1 
Screened Population 
All subjects who provided a signed informed consent form (ICF) will be included in the 
screened population. 
4.2 
Safety Population 
The safety population will include all enrolled subjects in the study. A subject will be 
considered enrolled in the study once the informed consent has been obtained and the 
subject meets all of the study inclusion criteria. Safety population will be used for both 
safety and efficacy analyses. 
4.3 
Pharmacokinetic (PK) Population  
The PK population will include all subjects who receive at least 1 dose of teduglutide in 
this SHP633-307 study and have at least 1 evaluable post-dose pharmacokinetic 
concentration value.   
5.
STUDY SUBJECTS
5.1 
Disposition of Subjects 
The number and percentage of subjects in each study analysis population (i.e., screened, 
safety and PK), and of which core studies were subjects transitioning from will be 
presented for the screened population.  
For the safety population, the number and percentage of subjects who completed or 
prematurely discontinued the study will be presented. Reasons for premature 
discontinuation from the study as recorded on the end of study page of the electronic case 
report form (eCRF) will be summarized (number and percentage). A subject data listing 
will present subject disposition for the safety population. 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Inclusion criteria violations, if any, will be presented in a listing for the screened 
population. 
5.2 
Demographic and Other Baseline Characteristics 
The baseline and demographic characteristics will be summarized for the safety 
population with 
descriptive 
statistics 
defined 
in 
Section 
11.1. 
Demographic 
and baseline characteristics to be presented include: 
•
Age (at informed consent date of core studies) in years, both as a continuous
parameter and by categories of <45, 45-<65, and ≥65.
•
Sex
•
Race
•
Ethnicity
•
Baseline Height (cm) of core studies (SHP633-306 and TED-C14-004)
•
Baseline Weight (kg) of core studies (SHP633-306 and TED-C14-004)
•
Baseline BMI (kg/m2) of core studies (SHP633-306 and TED-C14-004)
BMI is calculated as weight (kg)/ [height (m)]2. 
The following SBS history information collected at the first visit will be summarized 
with the descriptive statistics defined in Section 11.1 for subjects in the safety population 
whose SBS history were updated since the enrollment of the core studies and prior to the 
current study’s first visit: 
Any update in SBS history since core studies’ (SHP633-306 and TED-C14-004) screening 
visit will be collected and summarized. If there is no update in the SBS history from the 
core studies, the data from core studies screening visit will be used in the SBS history 
summary below. 
•
Duration of SBS at baseline of core studies (years)
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
•
Primary reason for the diagnosis of SBS (Crohn’s disease, vascular disease, injury,
volvulus, cancer, and other)
•
Secondary reason for the diagnosis of SBS (Y/N), secondary reason (Crohn’s
disease, vascular disease, injury, volvulus, cancer, and other)
•
Stoma (Y/N), stoma type (jejunostomy, ileostomy, colostomy, other)
•
Remaining colon (Y/N), estimated percent colon remaining, and colon in continuity
(Y/N)
•
Total estimated remaining small intestinal length (cm) and category (< 25 cm, ≥ 25
cm; < 40 cm, ≥ 40 cm; < 60 cm, ≥ 60 cm)
•
Distal/terminal ileum (Y/N) and ileocecal valve (Y/N)
•
Method to determine remaining anatomy length (surgery, radiology, and other)
Duration of SBS will be calculated as (date of ICF signed at core studies – date of diagnosis 
of SBS +1)/365.25. 
Partial dates for the start date of diagnosis of SBS will use the first day of the month if only 
the day is missing. If both the day and month are missing, the first of January will be used. 
5.3 
Medical History 
Medical and surgical history will supplement the medical history information collected at 
the start of the core studies (SHP633-306 and TED-C14-004) and will consist of the 
following: 
•
New medical conditions not related to SBS since core study participation
•
Ongoing adverse events at the time of core study completion
•
Update to a previously reported medical history
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Type of medical or surgical history, investigator verbatim as well 
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Page 15 of 40 
Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
as preferred terms (PT) and system organ class (SOC) will be included in the listings. The 
medical history will be summarized by SOC and PT within SOC for the safety population, 
with SOC sorted alphabetically and PT within SOC by descending incidence. 
5.4 
Concomitant Treatment and Medication 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  
All medications collected part of the extension study are concomitant medications.  
Medication use will be summarized by preferred name using the number and percentage 
of subjects for the Safety Population. Medications will be sorted categories alphabetically 
then by descending incidence by preferred name. Subjects with multiple occurrences of a 
medication in preferred name will only be counted once within each preferred name. A 
listing of all medications will be presented. The listing will be sorted by subject identifier 
and will include preferred name, reported name, dose, route of administration, dosing 
frequency, start date, end date, indication. 
Diagnostic, surgical, or therapeutic procedures during the study will be listed. 
5.5 
Exposure to Investigational Product 
The extent of exposure is defined as the number of days on treatment, including any periods 
of temporary dose interruption, calculated as: 
(date of last dose of SHP633-307 - date of first dose of SHP633-307) + 1. 
The first dose date and last dose date will be based on the eCRF. The extent of exposure, 
the number of days that the dose was administered, will be summarized with the 
descriptive statistics defined in Section 11.1. The number and percentages of subject will 
be tabulated for extent of exposure categorized months (<15, 15-<21, 21-<27, 27-<33, 
>=33).  Exposure summaries will be presented for the safety population.  
The total extent of exposure (core + extension combined) is defined as the number of days 
on treatment, including any periods of temporary dose interruption, calculated as: 
Extent of exposure in extension study + extent of exposure in core study.  
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
The total extent of exposure will be summarized with descriptive statistics and number and 
percentages of subjects based on months. 
The total extent of observation is defined as the number of days on study and calculated 
as:  
 (date of last visit/data cut-off date) - date of ICF of SHP633-307 + 1. 
The number and percentages of subject will be tabulated for total extent of observation 
categorized months (<24, 24-<30, 30-<36, 36-<42, >=42).   
5.6 
Measurements of Treatment Compliance 
Percent compliance will be calculated as 100 times the number of doses administered 
(either by the investigator or by the subject) divided by the number of days on treatment, 
excluding any periods of temporary dose interruptions due to adverse event that were 
deemed necessary by the investigator. Number of days on treatment is then calculated as 
(last dose date – first dose date +1) and the number of days of dose interruption due to 
adverse event will be excluded, i.e., the sum of (date of study drug resumed – start date of 
interruption due to adverse event) as recorded on the Study Drug Interruption eCRF form. 
The information whether the study treatment was administered is captured on the study 
drug administration daily diary. 
Drug accountability information, first dose date, last dose date, and study medication 
interruptions (start date of interruption, date study medication resumed, and reason for 
interruption) will be included in the listings.  
Subjects will be considered compliant overall for study medication if the calculated 
compliance is ≥ 80%. Overall treatment compliance will be presented for both percent 
compliance calculations using the descriptive statistics defined in Section 11.1 and the 
number and percentage of subjects who are ≥ 80% compliant for the safety population.
Treatment compliance by visit will not be calculated. 
5.7 
Protocol Deviations 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. 
Protocol deviations from the CTMS will be provided as part of the CTMS transfer to 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Biostatistics. Protocol deviations will be summarized for the safety population and all 
protocol deviations will be listed. 
6.
EFFICACY ANALYSES
All efficacy analyses will be based on the safety population and will be separated in two
columns based on subjects’ enrollment from the core studies (SHP633-306 and TED-C14-
004). For subjects transitioning from SHP633-306, data will be presented on a bi-monthly
basis through Month 24; thereafter, on every 3-monthly basis until EOS as defined
in Section 11.4. For subjects transitioning from TED-C14-004, data will be presented on
a 3-monthly basis until EOS as defined in Section 11.4.
All efficacy analyses will be descriptive only and there will be no statistical testing. 
6.1 
Analyses of Efficacy Endpoints 
The efficacy endpoints will be analyzed at each study visit and at the EOS, relative to the 
baseline of the core studies (SHP633-306 and TED-C14-004): 
Reduction in PN/IV volume of at least 20%
Absolute values and relative change in PN/IV volume
Complete weaning off PN/IV
Change in days per week of PN/IV
Change in plasma citrulline
Unless stated otherwise, the baseline for all efficacy analyses will be as defined in Section 
11.2. 
Analyses on weekly PN/IV volume are based on two data sources: the subject diary data 
and the investigator prescribed data.  
The diary PN/IV volume will be calculated based on the daily volumes recorded in 
subjects’ diaries within 14 days prior to each scheduled clinic and interim safety visit. The 
calculation will follow the formula below: 
Weekly volume = (sum of daily volumes in the diary/number of days with values) *7 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Missing daily PN/IV volumes will not be imputed. A maximum of 5 missing days (or at 
least 9 days of non-missing data) from the 14-day intervals are allowable, otherwise the 
interval will be classified as missing.  
Investigator prescribed data is captured in the PN/IV adjustment in eCRF. Investigator 
prescribed weekly PN/IV volume reported at each visit will be the most recent PN/IV 
prescription prior to or on the date of visit. 
Datasets and listings will include data collected at unscheduled visits. Data collected at 
unscheduled visits will not be included in summaries by timepoint or visit unless specified 
otherwise. 
Reduction of at least 20% in weekly PN/IV volume 
The number and percentage of subjects who achieved at least a 20% reduction from 
baseline of core studies (SHP633-306 or TED-C14-004) to each scheduled visit until EOS, 
in weekly PN/IV volume will be presented. 
Change in weekly PN/IV volume from baseline 
The absolute values and percent change in weekly PN/IV volume from baseline of core 
studies (SHP633-306 or TED-C14-004) to each scheduled visit until EOS, will be 
presented using the descriptive statistics defined in Section 11.1.  
Percent change in weekly PN/IV volume from baseline of core studies (SHP633-306 or 
TED-C14-004) at each scheduled visit until EOS will be calculated using the formula 
below:  
% change in weekly PN/IV volume at the visit = [(weekly PN/IV volume at the visit – 
weekly PN/IV volume at baseline) / weekly PN/IV volume at baseline] * 100 
95% confidence intervals of the mean will be generated for EOS as defined in Section 11.4. 
Mean ± standard error (SE) plots of absolute values and percent change from baseline in 
weekly PN/IV volume will be generated. In addition, individual absolute values and 
percent change from baseline in weekly PN/IV volume will be presented for each subject. 
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Statistical Analysis Plan Final v2.0 
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10Feb2022 
Number of subjects who are able to completely wean off PN/IV support 
A subject will be considered to have achieved independence from PN/IV (completely 
weaned off PN/IV) if the investigator prescribed no PN/IV at EOS and there is no use of 
PN/IV recorded in the subject diary during the 2 weeks prior to the last dosing visit. 
The number and percentage of subjects who completely wean off PN/IV will be presented.  
There will be a listing of those who completely weaned off PN/IV.   
Change in days per week of PN/IV support from baseline 
The absolute and percent change in days per week of PN/IV support from baseline of the 
core studies (SHP633-306 and TED-C14-004) to each scheduled visit until EOS, will be 
presented based on diary and investigator prescribed data using descriptive statistics 
defined in Section 11.1. 
Changes in plasma citrulline from baseline 
The absolute and percent change in plasma citrulline from baseline of the core studies 
(SHP633-306 and TED-C14-004) to each scheduled visit throughout the treatment 
period, as well as at EOS, will be presented using descriptive statistics defined in Section 
11.1. 
6.2 
Multiplicity Adjustment 
As there will be no statistical testing given the small sample size, no adjustment for 
multiple comparisons will be made. 
6.3 
Subgroup Analyses 
No subgroup analysis will be performed. 
7.
SAFETY ANALYSIS
The safety analysis will be performed using the safety population. Safety variables
include AEs, clinical laboratory variables, vital signs, ECG variables, physical
examination, 48-hour urine output and antibodies to teduglutide. For each safety
variable, the last value collected before the first dose of the investigational product of
core studies (SHP633-306 or TED-C14-004) will be used as the baseline for all analyses
of that safety variable.
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
7.1 
Adverse Events  
Adverse events will be coded using MedDRA. Investigator verbatim as well as PT and 
SOC will be included in the listings.  
Treatment emergent AEs (TEAEs) are defined as all AEs captured in this study. 
Treatment emergent AEs will be summarized overall using descriptive statistics (e.g., 
number and percentage of subjects). The number of events will also be presented. 
Categories summarized will include any TEAEs, severity of TEAEs, investigator 
assessment of relationship of TEAEs to study treatment, treatment emergent serious AEs 
(TESAEs), severity of TESAEs, investigator assessment of relationship of TESAEs to 
study treatment, TEAEs leading to death, TEAEs leading to study treatment 
discontinuation and TEAEs leading to study discontinuation. 
TEAEs will be summarized using number and percentage of subjects. Subject incidence 
for TEAEs within each SOC and PT will be presented, unless otherwise specified. The 
number of events will also be presented. Categories summarized are as follows: 

TEAEs,

Severity of TEAEs,

Investigator assessment of relationship of TEAEs to study treatment,

TESAEs.

Related TESAEs.
Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC 
by descending incidence. 
Listings will be provided for treatment emergent serious adverse events (TESAEs), TEAEs 
leading to death, TEAEs leading to study treatment discontinuation and TEAEs leading to 
study discontinuation. Adverse events leading to study discontinuation are not captured in 
the AE eCRF page, however primary reason for study discontinuation due to AE is 
captured in the End of Study eCRF page with the relevant AE number. This data will be 
used to present the AE leading to study discontinuation. The listings will be sorted by 
subject identifier and will include SOC, PT, reported term, start date/time, end date/time, 
frequency, severity, relationship, action taken, and outcome. 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
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TEAEs will be summarized by AE onset time in 3 months increments (6-<9 months, 9-<12 
months, 12-<15 months, etc.).  The denominator for each interval would be the number of 
subjects who reached same interval of treatment duration.   
AE onset time in months will be calculated as (AE start date – Date of first dose in SHP633-
306 or TED-C14-004 + 1) / 30.4375. The treatment duration in months, used for the 
denominators, will be calculated as (Last visit date – Date of first dose in SHP633-306 or 
TED-C14-004 + 1) / 30.4375.  
7.1.1 
Adverse Events of Special Interest 
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and 
immediate notification by the investigator to the sponsor is required. 
The AEs of special interest that require expedited regulatory reporting for this study include 
the following: 

Growth of preexisting polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not
limited to those of the GI or hepatobiliary system)
The preferred terms corresponding to each grouping of events of special interest will be 
identified by Takeda. A listing indicating the MedDRA terms corresponding to 
each grouping of events of special interest can be found in Appendix I. 
For each grouping of events of special interest, PT, the number and percentage of subjects 
with at least one TEAE of special interest will be presented. The number of events of 
special interest will also be summarized. 
Listing for TEAE of special interest will also be provided. 
7.2 
Clinical Laboratory Data 
Clinical laboratory tests are to be performed at site visits with results processed by a central 
laboratory. Laboratory tests to be performed during the treatment period can be found in 
Table 1. 
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Statistical Analysis Plan Final v2.0 
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Analyses will be presented in two columns based on subjects’ enrollment from the core 
studies (SHP633-306 and TED-C14-004). For subjects transitioning from SHP633-306, 
data will be presented on a bi-monthly basis through Month 24; thereafter, on every 3-
monthly basis until EOS as defined in Section 11.4. For subjects transitioning from TED-
C14-004, data will be presented on a 3-monthly basis until EOS. 
Laboratory parameters will be presented in standard international (SI) units. The 
summaries will be based on central lab results only. 
Quantitative results will be summarized for hematology, serum chemistry, and urinalysis 
parameters at each scheduled visit throughout the treatment period and at EOS. Both actual 
values and change from baseline will be summarized with descriptive statistics defined in 
Section 11.1. Unless stated otherwise, the baseline will be as defined in Section 11.2. 
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Statistical Analysis Plan Final v2.0 
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Table 1 
List of Laboratory Tests 
Hematology: 

Hematocrit

Hemoglobin

Platelet count

Red blood cell count

Red blood cell morphology, if
needed

White blood cell count with
differential
Urinalysis: 

Blood

Glucose

Leucocytes

Microscopic analysis

pH

Protein

Specific gravity

Urine Sodium
Pregnancy tests (females of 
childbearing potential): 

Urine β-HCG
Biochemistry: 

Albumin

Alkaline phosphatase

Alanine aminotransferase

Amylase

Aspartate aminotransferase

Bilirubin (total, direct and indirect)

Blood urea nitrogen

Calcium (total)

Chloride

Cholesterol

Citrulline (plasma)

C-reactive protein

Creatinine

Creatinine clearance

Gamma-glutamyl transferase

Glucose

Lipase

Magnesium

Phosphorus

Potassium

Sodium

Triglycerides

Uric acid
Clinical laboratory test values are markedly abnormal if they meet either the low or high 
markedly abnormal criterion listed in Table 2. The number and percentage of subjects 
with post-baseline markedly abnormal values will be summarized by parameter. Subjects 
with post-baseline markedly abnormal values at unscheduled visits will also be included 
in the summary. The percentages will be calculated relative to the number of subjects 
with at least 1 post-baseline assessment for the associated parameter. The numerator is 
the total number of subjects with at least 1 post-baseline markedly abnormal value. A 
supportive listing of subjects with post-baseline markedly abnormal values will be 
provided including the subject number, site, parameter, lab dates, baseline, and post-
baseline values. This listing will present all values for a subject and laboratory 
parameter if at least one post-baseline value for that subject and parameter is identified 
as being markedly abnormal. 
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Statistical Analysis Plan Final v2.0 
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Laboratory results will be presented in a listing for each lab panel (chemistry, hematology, 
and urinalysis) by subject, visit, and parameter. Laboratory values outside of the normal 
range will be flagged. Categorical urinalysis findings and urine pregnancy results will be 
presented in a listing only. 
Table 2: Markedly Abnormal Laboratory Criteria 
Lab parameter 
Unit 
Lower Limit 
Upper Limit 
Chemistry 
Albumin 
g/L 
<=20 
>=90 
Alkaline Phosphatase 
U/L 
NA 
>2*ULN
ALT 
U/L 
NA 
>3*ULN
Amylase 
U/L 
<=15 
>=350 
AST 
U/L 
NA 
>3*ULN
Bilirubin (total) 
μmol/L 
NA 
>2*ULN
BUN 
mmol/L 
NA 
>=10.7 
Calcium (total) 
mmol/L 
<=2.1 
>=3.0 
Chloride 
mmol/L 
<=80 
>=125 
Cholesterol (total) 
mmol/L 
NA 
>=12.9 
Creatinine 
μmol/L 
NA 
>=177 
C Reactive Protein 
mg/L 
NA 
>=21 
Glucose 
mmol/L 
<=1.7 
>=13.9 
Gamma glutamyl transferase 
U/L 
NA 
>100
Lipase 
U/L 
NA 
>3*ULN
Magnesium 
mmol/L 
<LLN 
>ULN
Phosphate 
mmol/L 
NA 
>=2.0 
Potassium 
mmol/L 
<=2.5 
>=6.5 
Sodium 
mmol/L 
<=120 
>=165 
Triglycerides 
mmol/L 
NA 
>=5.6 
Uric acid 
μmol/L 
NA 
>=624 (males)  
>=505 (females) 
Hematology 
Hematocrit 
L/L 
<=0.37 (males)  
<=0.32 (females) 
>0.54 (males)
NA (females)
Hemoglobin 
g/L 
<=115 (males)  
<=95 (females) 
NA 
Platelets 
109/L 
<=75 
>=700 
White Blood Cells 
109/L 
<=2.8 
>=16.0 
LLN = lower limit of normal, ULN = upper limit of normal 
ALT = Alanine Aminotransferase, Equivalent to SGPT 
AST = Aspartate Aminotransferase, Equivalent to SGOT 
BUN = Blood Urea Nitrogen 
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Statistical Analysis Plan Final v2.0 
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7.3 
Vital Signs, Body Weight and BMI 
The descriptive statistics defined in Section 11.1 will be used to summarize the vital signs 
(i.e., systolic blood pressure [mmHg], diastolic blood pressure [mmHg], pulse rate [bpm], 
body temperature [degree Celsius], weight [kg], and BMI [kg/m2]) at each scheduled visit 
throughout the treatment period and at EOS as defined in Section 11.4 for the 
safety population.  
Analyses will be presented in two columns based on subjects’ enrollment from the core 
studies (SHP633-306 and TED-C14-004). For subjects transitioning from SHP633-306, 
data will be presented on a bi-monthly basis through Month 24; thereafter, on every 3-
monthly basis until EOS. For subjects transitioning from TED-C14-004, data will be 
presented on a 3-monthly basis until EOS. 
Both actual values and changes from baseline will be summarized. Unless stated otherwise, 
the baseline will be as defined in Section 11.2. 
7.4 
Electrocardiogram 
The number and percentage of subjects with each type of ECG finding (Normal/Abnormal, 
Not Clinically Significant/Abnormal, Clinically Significant) will be presented at each 
scheduled visit throughout the treatment period and at EOS as defined in Section 11.4 for 
the safety population. All ECG data will be listed. 
Analyses will be presented in two columns based on subjects’ enrollment from the core 
studies (SHP633-306 and TED-C14-004). For subjects transitioning from SHP633-306, 
data will be presented on a six-monthly basis through Month 24 and at EOS. For subjects 
transitioning from TED-C14-004, data will only be presented at first visit and EOS.  
7.5 
Other Safety Data 
7.5.1 
Physical Examination 
Physical examination dates will be presented in a listing only.  New, clinically significant 
physical exam findings are recorded as adverse events.  
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7.5.2 
Antibodies to Teduglutide 
A summary table will provide the number of subjects with a sample analyzed at each 
scheduled visit and at EOS as defined in Section 11.4 for the safety population. 
The summary table will also provide the number of subjects with an antibody finding.  
Analyses will be based on subjects’ enrollment from the core studies (SHP633-306 and 
TED-C14-004). For subjects transitioning from SHP633-306, data will be presented on a 
six-monthly basis throughout the treatment period until EOS. For subjects transitioning 
from TED-C14-004, data will also be presented on a six-monthly basis throughout the 
treatment period until EOS. 
Observed value, change and percentage change from baseline for selected efficacy 
endpoints (Diary PS Volume, Prescribed PS Volume, Diary Days per Week of PS, 
Prescribed Days per Week of PS) will be analysed by antibody to teduglutide result 
(positive/negative) by semi-annually, relative to the baseline of the core study (SHP633-
306/TED-C14-004).  This by-visit analysis will be done for subjects with both efficacy 
endpoint and antibody data.  
All antibody data including neutralizing antibodies and antibody titers will be listed.  
7.5.3 
48 Hour Oral Fluid Intake and Urine Output 
Oral/enteral intake and urine output measurements collected during 48 hours prior to each 
scheduled visit and interim safety visit will be summarized throughout the treatment 
period and at EOS as defined in Section 11.4. Oral/enteral intake and urine output 
measurements for Day 1 and Day 2 will be captured in the eCRF. The average of 
Day 1 and Day 2 measurement in mL will be summarized. 
Analyses will be presented in columns based on subjects’ enrollment from the core studies 
(SHP633-306 and TED-C14-004). For subjects transitioning from SHP633-306, data will 
be presented on a bi-monthly basis through Month 24; thereafter, on every 3-monthly basis 
until EOS. For subjects transitioning from TED-C14-004, data will be presented on 3-
monthly basis until EOS. 
Actual values and both absolute and percent change from baseline will be summarized in 
the safety population with descriptive statistics defined in Section 11.1. 
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Statistical Analysis Plan Final v2.0 
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7.5.4 
Gastrointestinal-specific Testing 
Colonoscopy/Sigmoidoscopy 
Data for colonoscopy/Sigmoidoscopy collected during the treatment period will be 
summarized with the descriptive statistics defined in Section 11.1.  
Analyses will be presented in two columns based on subjects’ enrollment from the core 
studies (SHP633-306 and TED-C14-004). For subjects transitioning from SHP633-306, 
data will be presented for Visit 1, Month 24 and EOS as defined in Section 11.4. For 
subjects transitioning from TED-C14-004, data will be presented for Visit 1 and EOS. 
Esophagogastroduodenoscopy 
Data for EGD collected during the treatment period will be summarized with the 
descriptive statistics defined in Section 11.1.  
For subjects transitioning from SHP633-306, data will be presented for Visit 1, Month 24 
and EOS as defined in Section 11.4. For subjects transitioning from TED-C14-004, data 
will be presented for Visit 1 and EOS. 
8.
PHARMACOKINETIC ANALYSIS
8.1 
Pharmacokinetic Parameters 
The PK parameters will be derived and estimated based on measured teduglutide plasma 
concentrations using non-compartmental analysis (NCA) by a Takeda designated vendor 
in accordance with the PK SAP and generated separately. 
8.2 
Statistical Analysis of Pharmacokinetic Data 
The PK concentration data will be summarized on the PK population for the following 
scheduled sampling time points.  
Subjects enrolling from SHP633-306 at the first visit (Visit 1) in this study: 
0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but
at least 14 hours after the previous dose
1 hour postdose: ±10 minutes
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2 hours postdose: ±10 minutes
Subjects enrolling from TED-C14-004 at the first visit (Visit 1) in this study: 
0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but
at least 14 hours after the previous dose
15 minutes postdose: ±5 minutes
30 minutes postdose: ±5 minutes
1 hour postdose: ±10 minutes
2 hours postdose: ±10 minutes
3 hours postdose: ±10 minutes
4 hours postdose: ±30 minutes
6 hours postdose: ±30 minutes
8 hours postdose: ±30 minutes
10 hours postdose: ±30 minutes
12 hours postdose: ±30 minutes
Descriptive statistics of PK concentration (number of subjects, mean, standard deviation, 
coefficient of variation (CV) %, geometric mean, geometric CV (%), median, minimum 
and maximum values) will be calculated at each time point, and presented in two separated 
tables based on enrollment from core studies. Mean (±SD) PK concentration by time curves 
will be provided for the PK population. PK concentration by time will also be plotted by 
individual subject. A listing for PK concentration data will also be provided. 
9.
OTHER ANALYSES
The information related to the study drug training provided by the study physician will be
listed for all subjects in the safety population.
10.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE
An interim analysis will be conducted when the last subject who enters the study from
SHP633-306 reaches the Month 6 visit (Visit 7) and the last subject from TED-C14-004
reaches Visit 1. Additional interim analyses may be conducted during the study, as needed.
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Statistical Analysis Plan Final v2.0 
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Analyses will be descriptive in nature. No formal comparisons are planned and no 
hypotheses will be formally tested. Due to the open-label nature of this study, personnel 
involved in conducting the interim analyses will have access to treatment assignments.  
11.
DATA HANDLING CONVENTIONS
11.1 
General Data Reporting Conventions  
For subjects transitioning from SHP633-306 and TED-C14-004, the EOS visit assessments 
will be combined with the assessments for the first visit in SHP633-307.  
The small sample size resulting from the small study population requires the use of 
descriptive statistics with a goal of summarizing the sample and thus discourages the use 
of inferential statistics. 
Data from all study sites that participate in this protocol will be combined. 
Descriptive statistics will be presented as follows: 
•
Continuous variables, including those assessed on a discrete scale, will be summarized
using the following descriptive statistics:  the number of subjects, mean, median,
standard deviation, minimum, maximum and 95% confidence interval where needed.
The standard errors will be calculated in the tables if a corresponding figure is
generated (e.g., efficacy tables).
•
Categorical variables will be summarized by the number and percentage of subjects in
each category (with a category for missing data as needed). Unless otherwise stated,
the denominator for percentages is N (the number of subjects in the analysis
population).
The following rules will be followed for decimal places and rounding: 
•
Unless otherwise specified, means (arithmetic and geometric) and medians will be
rounded and presented to 1 decimal place more than the raw data and standard
deviations to 2 decimal places more than the raw data. Minimum and maximum values
will be presented to the same number of decimal places as the raw data.
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Statistical Analysis Plan Final v2.0 
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•
Unless otherwise specified, percentages should be presented to one decimal place.
Less than signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be
presented as < 0.1%, not 0.0%). This rule also applies to %CV.
•
BMI and duration of SBS should be rounded to 1 decimal place for reporting.
Study day will be calculated as follows: 
•
If the evaluation date is on or after the date of first day of study medication:
Study day = date of evaluation – first day of core studies’ study medication
+ 1
•
If the evaluation date is before the date of first day of study medication:
Study day = date of evaluation – first day of core studies’ study medication 
All output should have a 3-line header at the upper left margin: 
Takeda 
SHP633-307 
Confidential 
All output should have a 1-line footer with the SAS program name, including the path, and 
the date and time the output was produced at the lower left margin of the footer. 
Tables and listings should be internally paginated in relation to the total length for that 
table or listing (i.e., Page n of N, where n is the page number within the table or listing and 
N is the total number of pages for that table or listing). 
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines. 
A number should identify each table/listing, and the table designation (e.g., Table 14.x) 
should be centered above the title. A decimal system (e.g., x, x.y, x.y.z) should be used to 
identify tables/listings with related contents. The title should be centered and in mixed-case 
characters. The title and table/listing designation should be single-spaced but are separated 
from the content of the table/listing by a space and a solid underline. The study population 
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and/or subgroup (e.g., safety population) should be identified on the line immediately 
following the title. 
Column headings should be in title case characters. For numeric variables, the unit should 
be included in the column heading when appropriate. 
Footnotes should be single spaced but separated by an underline and a space from the text 
of the table/listing. The notes should be aligned vertically by the left vertical border of the 
table/listing. Numeric references, which can be confused with data, should not be used. 
Rather asterisks and other non-numeric symbols should be used to refer to footnotes. 
The dictionary (e.g., MedDRA, WHODD) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary. 
For both tables and listings where there are no observations (and hence there would be no 
output), the table/listing should be produced with all titles and footnotes as per its shell, but 
with the text showing no observations in the body of the output. 
Individual data listings will be sorted and presented by subject number and visit/event date. 
Dates will be presented using 8601 format. Dates with partial missing data will be 
presented with a dash (i.e., ‘-’) for the missing data (e.g., YYYY-MM---). 
For tables columns, subjects from the two core studies (i.e. SHP633-306 and TED-C14-
004) will be identified.
11.2 
Definition of Baseline 
For summary purposes, baseline values are taken from baseline values defined at the 
respective core studies (SHP633-306 and TED-C14-004). Baseline values will be obtained 
from the analysis datasets of the core studies. 
11.3 
Definition of Analysis Visit and Visit Windows 
Analysis visits will be used for all by-visit analysis.  This will be aligned with months of 
exposure on teduglutide from the core study.  This is achieved by aligning the first visit in 
the extension study to be equivalent to the last exposure month from the core study.  From 
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the first visit in the extension study, exposure month will be translated based on the nominal 
visits in the core study.  
The only exception would be PK analysis.  It will be based on protocol defined visits. 
Although there is a visit window of ± 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.   
Below tables are examples of visits in the extension studies corresponding to the analysis 
visits (i.e. nominal months of exposures in teduglutide). 
Analysis Visit 
Visit of Subject from 
SHP633-306 
Visit of Subject from 
TED-014-004  
Scenario 1 
Visit of Subject from 
TED-014-004 
Scenario 2 
Month 6 
Visit 1 
Month 7 
Visit 2 
Month 8 
Visit 3 
Month … 
Month 27 
Visit 22 
Month 28 
Visit 23 
Month 29 
Visit 24 
Month 30 
Visit 25* 
Month 31 
Month 32 
Month 33 
Visit 26 
Month 34 
Month 35 
Month 36 
Visit 27 
Month 37 
Month 38 
Month 39 
Visit 28 
Visit 1 
Month 40 
Month 41 
Month 42 
Visit 29 
Visit 2 
Visit 1 
Month 43 
Month 44 
Month 45 
Visit 30 
Visit 3 
Visit 2 
*Visiting frequency for subjects enrolled from SHP633-306 switch to every 3-month after Visit 25.
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11.4 
Derived Efficacy Endpoints 
An EOS time point is defined as the last determination of endpoint or last available 
measurement from the date of first dose, will be analyzed in addition to the scheduled visits. 
Unscheduled measurements will not be included in by-visit summaries but can contribute 
to the EOS value where applicable. 
11.5 
Handling of Missing, Unused, and Spurious Data  
No imputation for missing data (e.g., last observation carried forward) will be applied 
except for the partial dates to derive treatment emergent adverse events. 
Imputation will be performed for partial dates of AEs solely for the purpose of defining 
treatment emergence for AEs, determining whether an AE started in the treatment period 
and for calculating the onset time of adverse events. Details on how to handle partial dates 
for adverse events are described below.  
11.5.1 Missing Date of Investigational Product 
No imputation will be applicable to missing date of investigational product. 
11.5.2 Missing Date Information for Adverse Events  
If any AE records contain only partial dates, these will be handled by imputation, as 
described in the subsections below.  
11.5.2.1 Incomplete Start Date 
The following derivations will be applied to impute the missing dates. In each section, 
dates will be defined using the hierarchy of the derivations. Should any of the following 
start dates created be after a complete stop date provided, use the stop date as the start date, 
instead of the date that would otherwise be created. 
11.5.2.1.1 
Missing Day and Month 
1.
If only year is known, and it is previous to the year of the informed consent, use June
30th of that year.
2.
If only year is known, and it is the year of the first dose date, use the first dose date.
3.
If only year is known, and it is after the year of the first dose date, then use Jan 1st of
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that year. 
4.
If only year is known, and it is the year of the informed consent, use the informed
consent date.
11.5.2.1.2 
Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedures. 
11.5.2.1.3 
Missing Day Only 
1.
If year and month are known, and it is the month and year of the first dose date, use
the first dose date.
2.
If year and month are known, and it is the month and year of the informed consent, use
the informed consent date.
3.
If year and month are known, and the month is not the month and year of the first dose
or informed consent, use the first day of the month.
Otherwise, if a start date is unknown, leave as missing. 
11.5.2.2 Incomplete Stop Date  
No imputation is applied to incomplete stop date. 
11.5.3 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE 
starting on or after the date of the first dose of investigational product, then a severity of 
“Severe” will be assigned. The imputed values for severity assessment will be used for 
incidence summaries only and will not be reported in the data listings. 
11.5.4 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the 
date of the first dose of investigational product, a causality of “Related” will be assigned.
The imputed values for relationship to the investigational product will be used for incidence 
summaries only and will not be reported in the data listings. 
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11.5.5 Character Values of Clinical Laboratory Variables 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e. as “< X” or “> X” in the listings.
12.
ANALYSIS SOFTWARE
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS
Institute, Cary, NC, US) on SAS Grid in Windows Server 2012 environment.
13.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
There is no change of analysis from protocol.
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14.
REFERENCES
No references used in this SAP.
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15.
APPENDICES
Appendix I – MedDRA Terms Corresponding to Each Grouping of Adverse Event 
of Special Interest 
Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
Tumor promoting 
ability 
Neoplasms benign, 
malignant and 
unspecified 
Growth preexisting 
polyps 
Duodenal polyp 
Intestinal polyp 
Rectal Polyp 
Large intestine polyp 
Gastrointestinal polyp 
Benign neoplasia 
GI 
Gastrointestinal 
neoplasms benign 
Hepatic and biliary 
neoplasms benign 
Abdominal wall cyst 
Abdominal wall neoplasm 
benign 
Benign abdominal 
neoplasm 
Benign gastrointestinal 
neoplasm 
Benign mesenteric 
neoplasm 
Benign pancreatic 
neoplasm 
Benign peritoneal 
neoplasm 
Benign small intestinal 
neoplasm 
Gastric haemangioma 
Gastrointestinal polyp 
Gastrointestinal polyp 
haemorrhage 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
Gastrointestinal tract 
adenoma 
Gingival cyst 
Intestinal angioma 
Intestinal cyst 
Intestinal polyp 
Intra-abdominal 
haemangioma 
Intraductal papillary 
mucinous neoplasm 
Large intestine benign 
neoplasm 
Mesenteric cyst 
Pancreatic cyst 
Pancreatic cyst rupture 
Peutz-Jeghers syndrome 
Retroperitoneum cyst 
Small intestine polyp 
Stoma site polyp 
Adenolymphoma 
Ameloblastoma 
Benign salivary gland 
neoplasm 
Buccal polyp 
Cementoblastoma 
Dental cyst 
Gingival polyp 
Lip neoplasm benign 
Mouth cyst 
Odontogenic cyst 
Oral fibroma 
Oral haemangioma 
Oral neoplasm benign 
Oral papilloma 
Papillary cystadenoma 
lymphomatosum 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
Pleomorphic adenoma 
Salivary gland adenoma 
Salivary gland cyst 
Tongue cyst 
Tongue neoplasm benign 
Tongue polyp 
White sponge naevus 
Anal polyp 
Appendix adenoma 
Benign anorectal neoplasm 
Colon adenoma 
Large intestine fibroma 
Large intestine polyp 
Rectal adenoma 
Rectal polyp 
Benign duodenal neoplasm 
Benign gastric neoplasm 
Benign oesophageal 
neoplasm 
Duodenal polyp 
Gastric adenoma 
Gastric cyst 
Gastric leiomyoma 
Gastric polyps 
Oesophageal cyst 
Oesophageal papilloma 
Oesophageal polyp 
Biliary cyst 
Biliary polyp 
Choledochal cyst 
Congenital cystic disease 
of liver 
Gallbladder polyp 
Haemorrhagic hepatic cyst 
Hepatic cyst 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-307 
10Feb2022 
Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
Hepatic cyst infection 
Hepatic cyst ruptured 
Hepatobiliary cyst 
Benign biliary neoplasm 
Benign hepatic neoplasm 
Benign hepatobiliary 
neoplasm 
Benign neoplasm of 
ampulla of Vater 
Biliary adenoma 
Biliary hamartoma 
Cholangioadenoma 
Focal nodular hyperplasia 
Gallbladder adenoma 
Gallbladder papilloma 
Haemangioma of liver 
Hepatic adenoma 
Hepatic haemangioma 
rupture 
Hepatic hamartoma 
Note: MedDRA terms are based on MedDRA version 21.0. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Prot_000.pdf: 
Title: An Open-Label, Extension Study of Teduglutide in Japanese Subjects with Short 
Bowel Syndrome who Completed 24 Weeks of Treatment in SHP633-306 or 
TED-C14-004 
NCT Number: NCT03596164 
Protocol Approve Date: 06-Nov-2020 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


PROTOCOL: SHP633-307
TITLE:
An Open-Label, Extension Study of Teduglutide in Japanese Subjects 
with Short Bowel Syndrome who Completed 24 Weeks of Treatment in 
SHP633-306 or TED-C14-004
NUMBER
SHP633-307
PHASE
3 Extension
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
SPONSOR: 
Shire Human Genetic Therapies, Inc.
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-Chrome, Chuo-ku, Osaka-shi
Osaka
Japan
PROTOCOL 
HISTORY:
Amendment 2: 06 Nov 2020
Amendment 1: 27 Sep 2018
Original Protocol: 23 Jan 2018
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SHP633-307 Protocol Amendment 2
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06 Nov 2020
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES..................................................................................................................16
1
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options.........................................................21
1.2
Product Background and Clinical Information ..................................................22
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2.1
Rationale for the Study.......................................................................................24
2.2
Study Objectives ................................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ............................................................................25
3.2
Duration and Study Completion Definition .......................................................25
3.3
Sites and Regions ...............................................................................................25
4
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria................................................................................................27
4.2
Exclusion Criteria...............................................................................................27
4.3
Reproductive Potential .......................................................................................27
4.4
Discontinuation of Subjects ...............................................................................27
4.4.1
Reasons for Discontinuation..................................................................................28
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................28
5
CONCOMITANT TREATMENT..........................................................................................29
5.1
Concomitant Treatment......................................................................................29
5.1.1
Permitted Treatment...............................................................................................29
5.1.2
Prohibited Treatment .............................................................................................29
6
INVESTIGATIONAL PRODUCT ........................................................................................30
6.1
Identity of Investigational Product.....................................................................30
6.1.1
Blinding the Treatment Assignment......................................................................30
6.2
Administration of Investigational Product .........................................................30
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6.2.1
Allocation of Subjects to Treatment ......................................................................30
6.2.2
Dosing....................................................................................................................30
6.2.2.1
Subject Administration...........................................................................30
6.2.3
Unblinding the Treatment Assignment..................................................................31
6.3
Labeling, Packaging, Storage, and Handling .....................................................31
6.3.1
Labeling and Packaging.........................................................................................31
6.3.2
Storage and Handling.............................................................................................32
6.4
Drug Accountability...........................................................................................33
6.5
Subject Compliance............................................................................................34
7
STUDY PROCEDURES........................................................................................................35
7.1
Study Schedule...................................................................................................35
7.1.1
First Visit ...............................................................................................................35
7.1.2
Treatment Period....................................................................................................35
7.2
Study Evaluations and Procedures .....................................................................35
7.2.1
Efficacy Assessments.............................................................................................35
7.2.1.1
Subject Diaries .......................................................................................35
7.2.1.2
Prescribed Parenteral Nutrition ..............................................................36
7.2.1.3
Plasma Citrulline....................................................................................36
7.2.2
Safety Assessments................................................................................................36
7.2.2.1
Laboratory Evaluations ..........................................................................36
7.2.2.2
Antibodies to Teduglutide......................................................................37
7.2.2.3
Physical Examinations ...........................................................................38
7.2.2.4
Vital Signs, Body Weight, and Height...................................................38
7.2.2.5
Electrocardiograms.................................................................................38
7.2.2.6
Gastrointestinal-specific Testing............................................................38
7.2.2.7
48-Hour Oral Fluid Intake and Urine Output.........................................39
7.2.3
Pharmacokinetic Assessments ...............................................................................39
7.3
Changes to Study Procedures Due to a Pandemic..............................................40
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................42
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events...................................................................................................42
8.1.1
Severity Categorization..........................................................................................42
8.1.2
Relationship Categorization...................................................................................43
8.1.3
Outcome Categorization ........................................................................................43
8.1.4
Symptoms of the Disease under Study ..................................................................44
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................44
8.1.6
Pregnancy...............................................................................................................44
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................45
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8.2
Serious Adverse Event Procedures ....................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................46
8.2.4
Serious Adverse Event Collection Time Frame.....................................................47
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................47
8.2.6
Fatal Outcome........................................................................................................47
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site       
Reporting................................................................................................................47
8.3
Adverse Events of Special Interest.....................................................................48
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................49
9.1
Data Collection...................................................................................................49
9.2
Clinical Data Management.................................................................................49
9.3
Statistical Analysis Process................................................................................49
9.4
Planned Interim Analysis ...................................................................................49
9.5
Sample Size Calculation and Power Considerations..........................................50
9.6
Study Population ................................................................................................50
9.7
Efficacy Analyses...............................................................................................50
9.8
Safety Analyses..................................................................................................51
9.9
Pharmacokinetics Analyses................................................................................51
10 SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................52
10.1
Sponsor’s Responsibilities .................................................................................52
10.1.1 Good Clinical Practice Compliance.......................................................................52
10.1.2 Indemnity/Liability and Insurance.........................................................................52
10.1.3 Public Posting of Study Information......................................................................52
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of  Member States Concerned and Ethics Committees..........................................52
10.1.5 Study Suspension, Termination, and Completion..................................................53
10.2
Investigator’s Responsibilities ...........................................................................53
10.2.1 Good Clinical Practice Compliance.......................................................................53
10.2.2 Protocol Adherence and Investigator Agreement..................................................53
10.2.3 Documentation and Retention of Records.............................................................54
10.2.3.1
Electronic Case Report Forms................................................................54
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................54
10.2.3.3
Audit/Inspection.....................................................................................54
10.2.3.4
Financial Disclosure...............................................................................55
10.3
Ethical Considerations........................................................................................55
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10.3.1 Informed Consent...................................................................................................55
10.3.2 Institutional Review Board or Ethics Committee..................................................55
10.4
Privacy and Confidentiality................................................................................56
10.5
Study Results/Publication Policy .......................................................................56
11 REFERENCES .......................................................................................................................58
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06 Nov 2020
LIST OF TABLES
Table 1
Schedule of Evaluations and Procedures for Subjects Enrolling from 
SHP633-306 ..................................................................................................16
Table 2
Schedule of Evaluations and Procedures – For Subjects Enrolling from 
TED-C14-004................................................................................................19
Table 3
Prohibited Treatment.....................................................................................29
Table 4
List of Laboratory Tests ................................................................................37
LIST OF FIGURES
Figure 1
SHP633-307 Study Schematic ......................................................................26
LIST OF APPENDICES
Appendix 1
Appendix 2
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Teduglutide
06 Nov 2020
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation
Definition
AE
adverse event
AUC
area under the plasma concentration-time curve
AUC0–t
AUC from zero to the last measurable concentration
BUN
blood urea nitrogen
CL/F
apparent clearance
Cmax
maximum plasma concentration
COVID-19
coronavirus disease 2019
CRO
contract research organization
ECG
electrocardiogram
eCRF
electronic case report form
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
ICMJE
International Committee of Medicinal Journal Editors
ICH
International Committee on Harmonisation
I/O
oral fluid intake and urine output
IRB
Institutional Review Board
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN/IV
parenteral nutrition/intraveneous
PNALD
parenteral nutrition-associated liver disease
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
ULN
upper limit of normal 
US
United States
V/F
apparent volume of distribution
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06 Nov 2020
STUDY SYNOPSIS
Protocol number: SHP633-307
Drug: Teduglutide
Title of the study: An Open-Label, Extension Study of Teduglutide in Japanese Subjects with Short Bowel 
Syndrome who Completed 24 Weeks of Treatment in SHP633-306 or TED-C14-004
Number of subjects (total and for each treatment arm):
Approximately 5 subjects who completed Study SHP633-306 and up to 7 subjects in TED-C14-004 may enroll in 
this extension study.
Investigator(s): Multicenter study.
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 sites in Japan.
Study period (planned):
2018-2021
Clinical phase:
3 Extension
Objectives:
The objectives of this clinical study are to evaluate the long-term safety and efficacy of teduglutide in Japanese 
subjects with parenteral nutrition/intravenous (PN/IV)-dependent short bowel syndrome (SBS) who completed 
SHP633-306 or who were in the extension phase of TED-C14-004 study.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg subcutaneously (SC) once daily into 1 of the 4 quadrants of the abdomen or either thigh 
or arm.
The Site Training Guide specifies the process for training subjects and measures to be taken to provide oversight 
on study drug administration.
Methodology:
This will be a long-term extension study to evaluate the safety and efficacy of teduglutide in Japanese subjects 
who completed Study SHP633-306 or were in the extension phase of TED-C14-004 (core studies).
Once informed consent has been obtained, demographics, updates to medical history and short bowel syndrome 
history will be obtained. Teduglutide 0.05 mg/kg will be administered once daily until teduglutide is 
commercially available, or the subject’s participation in this study is discontinued, or the study is discontinued. At 
each site visit, efficacy (adjustments to PN/IV) and safety will be monitored.
For subjects transitioning from SHP633-306, the SHP633-306 EOS visit assessments will be combined with the 
assessments for the first visit in SHP633-307. Clinic and phone visits will then alternate on a monthly basis 
through Month 24; thereafter, clinic visits will occur every 3 months. For subjects transitioning from 
TED-C14-004, the TED-C14-004 EOS visit assessments will be combined with the assessments for the first visit 
in SHP633-307; thereafter clinic visits will occur every 3 months.
Subjects enrolling from TED-C14-004 will have blood samples taken for teduglutide pharmacokinetic (PK)
analysis at predose and at 15, 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the first visit that they 
enter in this study. Subjects enrolling from SHP633-306 will have blood samples taken for teduglutide PK 
analysis at predose and 1 and 2 hours post dose at the first clinic visit in this study. 
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06 Nov 2020
Endpoints:
Efficacy
The following efficacy endpoints will be assessed at each visit relative to the baseline visit of the relevant core 
study (SHP633-306 or TED-C14-004):

Reduction in PN/IV volume of at least 20%

Absolute and relative change in PN/IV volume

Complete weaning off PN/IV

Change in days per week of PN/IV

Change in plasma citrulline
Pharmacokinetics
The following parameters will be derived as appropriate (for subjects with rich PK sample collection): area under 
the plasma concentration-time curve from zero to the last measurable concentration (AUC0–t); maximum plasma 
concentration (Cmax); time to Cmax (tmax); terminal-phase half-life (t1/2); apparent clearance (CL/F); and apparent 
volume of distribution (V/F).
Safety
Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory safety data, antibodies to 
teduglutide, and changes in 48 hour urine output, body weight and body mass index (BMI) will be evaluated. 
Colonoscopy/sigmoidoscopy will be repeated at Month 24/early termination (ET) and EOS/ET.
Statistical Methods:
Efficacy
Efficacy endpoints will be analyzed at each study visit and at the end of study [EOS]), relative to the baseline of 
the core studies (SHP633-306 and TED-C14-004).
The absolute and percent change in weekly PN/IV volume, days per week of PN/IV support, and plasma citrulline 
from baseline to each scheduled visit, as well as at EOS, will be summarized using descriptive statistics. The 
number and percentage of subjects who demonstrate reduction in PN/IV volume of 20% will also be summarized.
The number and percentage of subjects who completely wean off PN/IV support by EOS will be summarized. A 
subject will be considered to have achieved from PN/IV (completely weaned off PN/IV) if the investigator 
prescribes no PN/IV at EOS and there is no use of PN/IV recorded in the subject diary during the 2 weeks prior to 
the last dosing visit.
Pharmacokinetics
Teduglutide plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, minimum, median, and maximum) at nominal time points. Pharmacokinetic parameters will be 
estimated using non-compartmental analysis as appropriate and summarized using descriptive statistics (number, 
mean, standard deviation, geometric mean, and CV%, minimum, median, and maximum).
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
Treatment-emergent AEs are defined as AEs that started or worsened on or after the date and time of the first 
dose of study dose. Treatment-emergent AEs will be summarized by system organ class and preferred term using 
descriptive statistics (eg, number and percentage of subjects). Adverse events will be summarized by severity, 
relationship to treatment, and for AEs of special interest, AEs leading to discontinuation, and AEs leading to 
death. Serious AEs will also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, ECG variables, and descriptive statistics 
(eg, n, mean, standard deviation, median, minimum and maximum values, the number and percentage of subjects 
in specified categories) will be used to summarize the absolute values and change from baseline at each time 
point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
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06 Nov 2020
STUDY SCHEDULES
Table 1
Schedule of Evaluations and Procedures for Subjects Enrolling from SHP633-306
Procedures
First 
Visita 
Mo 
1/13b
Mo 
2/14
Mo 
3/15b
Mo 
4/16
Mo 
5/17b
Mo 
6/18
Mo 
7/19b
Mo 
8/20
Mo 
9/21b
Mo 
10/22
Mo 
11/23b
Mo 
12
Mo 
24 
Every 
3-Month
Visitc
EOS/
ET
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
V26d, 
V27, etc
EOS/
ET
Visit Window 
(days) 
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Informed 
consent
X
Eligibility
X
Medical 
historye
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine 
pregnancyf
X
X
X
X
X
X
X
X
X
X
Physical 
examinationg
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
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
X
X
Safety 
laboratory tests
X
X
X
X
X
X
X
X
X
X
12-lead ECG
Xh
X
X
X
X
EGDi
X
X
X
Colonoscopy/ 
sigmoidoscopy 
Xj
X
X
Citrulline
X
X
X 
X
(X)
X
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06 Nov 2020
Table 1
Schedule of Evaluations and Procedures for Subjects Enrolling from SHP633-306
Procedures
First 
Visita 
Mo 
1/13b
Mo 
2/14
Mo 
3/15b
Mo 
4/16
Mo 
5/17b
Mo 
6/18
Mo 
7/19b
Mo 
8/20
Mo 
9/21b
Mo 
10/22
Mo 
11/23b
Mo 
12
Mo 
24 
Every 
3-Month
Visitc
EOS/
ET
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
V26d, 
V27, etc
EOS/
ET
Visit Window 
(days) 
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Antibodies to 
teduglutidek
X
X
X
X
(X)
X
PK sampling
Xl
Drug 
dispensing
X
X
X
X
X
X
X
X
X
Interim safety 
visitm
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Dispense Diaryn
X
X
X
X
X
X
X
X
X
Review Diaryo
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
[X]
X
X
X
X
Record PN/IV
use and adjust 
prescription as 
indicated
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Teduglutide 
dosing
Xp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirm 
administration 
proficiency
X
X
X
X
X
Complianceq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=assessment to be performed only every other visit (every 6 months); [X] = Possible interim safety evaluation time point; 48-hour I/O=48-hour fluid intake/urine output;
BMI=body mass index; ECG=electrocardiogram; EGD=esophagogastroduodenoscopy; EOS=end of study; EOT=end of treatment; ET=early termination; L=liter; Mo=month; 
PK=pharmacokinectic; PN/IV=parenteral nutrition/intravenous; V=visit
Note: Clinic visits will alternate with phone visits on a monthly basis for the first 24 months of the extension study for subjects enrolling from SHP633-306.
a The last visit for SHP633-306 is combined with the first visit for SHP633-307. 
b Subject does not need to visit the clinic. Assessments can be completed over the telephone.
c Subjects will undergo a clinic visit every 3 months until teduglutide is commercially available, the subject’s participation in this study is discontinued, or the study is 
discontinued.
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Table 1
Schedule of Evaluations and Procedures for Subjects Enrolling from SHP633-306
Procedures
First 
Visita 
Mo 
1/13b
Mo 
2/14
Mo 
3/15b
Mo 
4/16
Mo 
5/17b
Mo 
6/18
Mo 
7/19b
Mo 
8/20
Mo 
9/21b
Mo 
10/22
Mo 
11/23b
Mo 
12
Mo 
24 
Every 
3-Month
Visitc
EOS/
ET
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
V26d, 
V27, etc
EOS/
ET
Visit Window 
(days) 
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
d Visit 26 will occur 3 months after Visit 25.
e Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of SHP633-306, and events that occurred during the 
period between completion of SHP633-306 and informed consent to SHP 633-307.
f For women of childbearing potential.
g Full physical examination to be performed at V1, V12, V24, and annually thereafter (V28, V32, V36, etc), and at the EOS/ET visit; a focused examination may be performed 
at all other clinic visits.
h Electrocardiogram will be conducted for the EOT visit on the previous study (SHP633-306) and if done, the test will not need to be repeated. If the ECG was not conducted for 
SHP633-306 EOT then the ECG must be conducted within +7 days of the Visit 1 date.
i In subjects with risk factors for gastric cancer, EGD is performed at the first clinic visit (V1), Month 24 (V25), and EOS/ET (see Section 7.2.2.6). If the EGD was not 
conducted for SHP633-306 EOT then the EGD must be conducted within +7 days of the Visit 1 date.
jColonoscopy/sigmoidoscopy will be conducted for the EOT visit on the previous study (SHP633-306) and if done, the test will not need to be repeated. If the 
colonoscopy/sigmoidoscopy was not conducted for SHP633-306 EOT then the colonoscopy/sigmoidoscopy must be conducted within +7 days of the Visit 1 date.
k Sample for antibody testing must be drawn at least 14 hours after dosing. 
lSubjects enrolling from SHP633-306 will have blood samples taken for PK analysis at predose and 1 and 2 hours post dose at the first clinic visit (V1). If a subject is unable to
provide blood samples for PK at the first clinic visit (Visit 1), PK samples can be collected up to 5 days after Visit 1.
m Interim safety evaluations will be performed 5 to 7 days after any change to the subject’s PN/IV volume is implemented. Hemoglobin, hematocrit, serum blood urea nitrogen,
creatinine, and urine sodium will be measured.
n The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
o All subjects will measure 48-hour oral fluid intake and urine output at home immediately prior to the each scheduled visit and interim safety visit. Diary data from the core
study may be used for the subject’s assessments when entering the SHP633-307 study.
p The dose of study drug administered at time of entry may be adjusted based on change in the subject’s weight from baseline of SHP633-306.
q 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.
Note: The next scheduled visit should be based on the previous visit, not on Visit 1.
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Table 2
Schedule of Evaluations and Procedures – For Subjects Enrolling from 
TED-C14-004
Procedures
First Visita
Every 3-Month Visitb
EOS/ET 
Visit Number:
V1
V1, V2, etc
EOS/ET
Visit Window (days) 
± 7
± 7
Informed consent
X
Eligibility
X
Medical historyc
X
Adverse events
X
X
X
Urine pregnancy testd
X
X
X
Physical examinatione
X
X
X
Vital signs
X
X
X
Body weight
X
X
X
Height
X
Concomitant medications
X
X
X
Safety laboratory tests
X
X
X
12-lead ECG
Xf
X
EGDg
X
X
Colonoscopy/sigmoidoscopy
Xh
X
Citrulline
X
(X)
X
Antibodies to teduglutidei
X
(X)
X
PK sampling
Xj
Drug dispensing
X
X
Interim safety visit k
[X]
[X]
[X]
Dispense diaryl
X
X
Review Diarym
X
X
X
Record PN/IV use and adjust 
prescription as indicated
X
X
X
Teduglutide dosing
Xn
X
Confirm administration 
proficiency
Xo
Xo
Xo
(X)
Compliancep
X
X
X
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Table 2
Schedule of Evaluations and Procedures – For Subjects Enrolling from 
TED-C14-004
Procedures
First Visita
Every 3-Month Visitb
EOS/ET 
Visit Number:
V1
V1, V2, etc
EOS/ET
Visit Window (days) 
± 7
± 7
(X)=assessment to be performed only every other visit (every 6 months); [X]=possible interim safety evaluation time point; 
BMI=body mass index; ECG=electrocardiogram; EGD=esophagogastroduodenoscopy; EOS=end of study; EOT=end of 
treatment; ET=early termination; L=liter; PK=pharmacokinetic; PN/IV=parenteral nutrition/intravenous; T=time
Note: Study visits will be scheduled every 3 months throughout SHP633-307. 
a Assessments for the last visit for TED-C14-004 are combined with the assessments for first visit in SHP633-307, but labs for 
TED-C14-004 EOS and SHP633-307 V1 need to be drawn for each study. 
b Subjects will undergo a clinic visit every 3 months until teduglutide is commercially available, the subject’s participation in this 
study is discontinued, or the study is discontinued.
c Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of 
TED-C14-004, and events that occurred during the period between completion of TED-C14-004 and informed consent to SHP 
633-307.
d For women of childbearing potential.
e Full physical examination to be performed at V1 and annually thereafter (V5, V9, V13, etc), and at EOS (or ET) visit; a focused
physical examination will be performed at all other study visits.
f Electrocardiogram will be conducted for the EOT visit on the previous study (TED-C14-004) and if done, the test will not need
to be repeated. If the ECG was not conducted for TED-C14-004 EOT then the ECG must be conducted within +7 days of the
Visit 1 date.
g Esophagogastroduodenoscopy should be completed at Visit 1 (or conducted within +7 days of the Visit 1 date) for all subjects
entering from TED-C14-004. Esophagogastroduodenoscopy is required at EOS/ET for subjects with risk factors for gastric
cancer (see Section 7.2.2.6).
h Colonoscopy/sigmoidoscopy will be conducted for the EOT visit on the previous study (TED-C14-004) and if done, the test
will not need to be repeated. If the colonoscopy/sigmoidoscopy was not conducted for TED-C14-004 EOT then the
colonoscopy/sigmoidoscopy must be conducted within +7 days of the Visit 1 date.
iSample for antibody testing must be drawn at least 14 hours after dosing.
j Subjects enrolling from TED-C14-004 will have blood samples taken for teduglutide PK analysis at predose and at 15, 30
minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the first visit in this study. If a subject is unable to provide blood
samples for PK at the first clinic visit (Visit 1), PK samples can be collected up to 5 days after Visit 1.
k Interim safety evaluations will be performed 5 to 7 days after a change to PN/IV volume is implemented.
Hemoglobin/hematocrit, serum blood urea nitrogen and serum creatinine, and urine sodium will be measured.
l The diary is to be completed for the 2-week period prior to every clinic or telephone visit.
m 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. Diary data from the core study may be used for the subject’s assessments when entering the SHP633-307
study.
n The dose of study drug administered at time of entry may be adjusted based on change in the subject’s weight from baseline of
TED-C14-004.
o The study physician must observe the subject administering the study drug in compliance with the study drug administration
checklist at least twice before the subject is allowed to administer the drug without direct observation by the physician. Refer to
the criteria for self-administration in the Site Training Guide.
p 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.
Note: The next scheduled visit should be based on the previous visit, not on Visit 1.
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare, serious, disabling, socially incapacitating and potentially 
life-threatening condition which is the leading cause of intestinal failure (Nightingale and 
Woodward 2006; Pironi et al. 2015). Intestinal failure from SBS results from surgical resection 
or congenital defects and is defined as the reduction of gut function below the minimum 
necessary for the absorption of macronutrients and/or water and electrolytes, such that 
intravenous supplementation is required to maintain health and/or growth. Patients with SBS are 
highly prone to malnutrition, diarrhea, dehydration, and an inability to maintain weight due to 
the reduced intestinal capacity to absorb macronutrients, water, and electrolytes (Dudrick et al. 
1991; Nightingale 1999; Rombeau and Rolandelli 1987; Shanbhogue and Molenaar 1994;
Vanderhoof and Langnas 1997; Wilmore et al. 1997). Additional potential consequences of SBS 
include dehydration, electrolyte disturbances, malabsorption of nutrients, gastric hypersecretion, 
metabolic acidosis, cholelithiasis, nephrolithiasis, steatorrhea, diarrhea, small bowel bacterial 
overgrowth and weight loss (Nightingale and Woodward 2006; O'keefe et al. 2006).
Following resection, intestinal adaptation may occur in adults during the first 1 to 2 years 
postsurgery. The adaptive response characterized by mucosal hyperplasia, increased mucosal 
blood flow, improved segmental absorption and increased hepatobiliary secretions (O'keefe et al. 
2006). These morphologic and functional changes are coordinated by the release of 
glucagon-like peptide 2 (GLP-2) from L-type enteroendocrine cells. In response to lumenal 
nutrients reaching the distal ileum and colon, L-cells secrete GLP-2, which regulates 
gastrointestinal secretions, motility, and the local production of additional hormones, cytokines, 
and growth factors.
The clinical care of SBS is mainly supportive and focuses on optimizing remnant intestinal 
function through dietary interventions, oral rehydration solutions, antidiarrheal and antisecretory 
agents. Despite intestinal adaptation following resection, many SBS develop intestinal failure, 
characterized by the requirement for chronic use of parenteral nutrition/intravenous (PN/IV) or 
other intravenous fluids to maintain hydration, electrolyte balance, and/or nutritional needs. 
Although PN/IV can meet basic nutrition and fluid requirements, it does not improve the body's 
ability to absorb nutrients. Parenteral nutrition/intravenous dependence is associated with 
shortened life span (Messing et al. 1999; Scolapio et al. 1999), life threatening complications (eg, 
sepsis, blood clots, or liver damage), as well as reduced quality of life (Delegge et al. 2007;
Jackson and Buchman 2005; Jeppesen 2006). The development of parenteral nutrition-associated 
liver disease (PNALD) predisposes patients to sepsis, increased mortality rates, and the potential 
to develop irreversible liver damage (Tazuke and Teitelbaum 2009). The American 
Gastroenterological Association Medical Position Statement on Short Bowel Syndrome 
recommends that management of PNALD should include reduction of toxic PN/IV constituents 
such as phytosterols, a component of soy-based lipid emulsions (American Gastroenterological 
Association 2003).
The severity of SBS is illustrated by the shortened life-span in patients with moderate to severe 
disease (Messing et al. 1999). In SBS, survival can be impacted by the underlying condition, by 
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severe clinical manifestations of malabsorption, and treatment-associated life-threatening 
complications (O'keefe et al. 2006). With current medical management practices, the overall 
10 year survival in SBS patients is 52%, and is significantly lower in patients who remain 
chronically PN/IV-dependent compared to patients who wean off PN/IV (40.7% versus 67%) 
(Amiot et al. 2013). 
In addition, the symptoms of SBS and the inconveniences and complications in relation to PN/IV
support may cause potential restrictions in the lifestyle of these patients leading to significant 
impairment of their quality of life (Jeppesen et al. 1999; Baxter et al. 2006; Winkler and Smith 
2014). The impact of SBS and PN/IV on quality of life may be significant with patients, on 
average, moving their bowels at least 10 times a day, with multiple ostomy bag changes per day, 
and having a typical output of 2 to 3 liters of watery diarrhea per day. Patients may be on PN/IV
10 to 15 hours a day for up to 7 days a week. Sleep is disrupted and patients typically cannot 
work.
1.2
Product Background and Clinical Information
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 and therefore maintains a longer elimination 
half-life of approximately 2 hours in healthy subjects and 1.3 hours in adult SBS subjects 
compared to the native peptide, which has a t1/2 of approximately 7 minutes. Teduglutide has 
been shown in animal studies and previous human clinical trials to increase villus height and 
crypt depth in the intestinal epithelium, thereby increasing the absorptive surface area of the 
intestines. 
Results of the pivotal study, CL0600-020, showed that teduglutide at a dose of 0.05 mg/kg/day 
for up to 24 weeks was superior to placebo in reducing PN/IV support in adult subjects with 
SBS. In this study the responder rate (defined as at least a 20% reduction from baseline in
weekly PN/IV volume at Week 20 and Week 24) was 62.8% in the teduglutide 0.05 mg/kg/day 
group with subjects achieving a mean reduction from baseline in PN/IV volume of 4.4 L/week at 
Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/IV volume reduction, gaining additional days off per week, and achieving complete weaning 
of parenteral support. The most significant reductions were for those subjects who received 
24 weeks of teduglutide 0.05 mg/kg/day in CL0600-020 and continued treatment in CL0600-021 
for another 24 months. In this cohort, 10 subjects completely weaned off of PN/IV support and 
18/30 (60.0%) had a reduction in their PN/IV requirement of at least 3 days per week. It was 
encouraging that efficacy was also observed for subjects who initiated treatment in CL0600-021 
(ie, those who received placebo or were not treated in CL0600-020). 
After only 6 months of treatment, 37.1% of subjects who had received placebo in CL0600-020 
had at least a 20% reduction in weekly PN/IV volume, which increased to 55.2% by Month 24. 
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Two of these subjects completely weaned off of their PN/IV support. In subjects who had not 
been treated in CL0600-020, 50.0% had at least a 20% reduction in weekly PN/IV volume after 
6 months of treatment, which increased to 66.7% by Month 24. One of these subjects completely 
weaned off of their PN/IV support. Overall, a total of 13 subjects achieved enteral autonomy 
(independence of PN/IV support), and 25/65 (38.5%) subjects demonstrated a reduction of 
≥3 days/week in their 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 support the efficacy of long-term treatment with teduglutide in 
PN/IV-dependent SBS subjects.
Teduglutide (0.05 mg/kg/day) is currently indicated for the treatment of adult patients with SBS. 
The European Commission granted a centralized marketing authorization valid throughout the 
European Union (EU) for teduglutide (REVESTIVE®) on 30 Aug 2012. On 29 Jun 2016, the 
European Commission granted an extension of the Market Authorization for teduglutide for the 
treatment of patients aged 1 year and above with SBS. A New Drug Application for teduglutide 
(GATTEX®) was approved by the United States (US) Food and Drug Administration (FDA) on 
21 Dec 2012. Teduglutide is currently approved in >30 countries.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the EU and the US. The clinical profile and medical issues related to 
SBS and PN/IV in Japan are similar to those in the EU and US. Therefore, there is an unmet 
medical need for Japanese patients with PN/IV-dependent SBS. This study is designed to provide 
evidence of long-term safety and efficacy of teduglutide in a Japanese SBS patient population.
2.2
Study Objectives
The objectives of this clinical study are to evaluate the long-term safety and efficacy of 
teduglutide in Japanese subjects with PN/IV-dependent SBS who completed SHP633-306 or 
who were in the extension phase of the TED-C14-004 study.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This will be a long-term extension study to evaluate the safety and efficacy of teduglutide in 
Japanese subjects who completed Study SHP633-306 or were in the extension phase of 
TED-C14-004 (core studies). A schematic representation of the study design is presented in 
Figure 1. 
Once informed consent has been obtained, demographics, updates to medical history and short 
bowel syndrome history will be obtained. Teduglutide 0.05 mg/kg will be administered once 
daily until teduglutide is either commercially available, or the subject’s participation in this study 
is discontinued, or the study is discontinued. At each site visit, efficacy (adjustments to PN/IV) 
and safety will be monitored.
For subjects transitioning from SHP633-306, the SHP633-306 EOS visit assessments will be 
combined with the assessments for the first visit in SHP633-307. Clinic and phone visits will 
then alternate on a monthly basis through Month 24; thereafter, clinic visits will occur every 
3 months (Table 1). For subjects transitioning from TED-C14-004, the TED-C14-004 EOS visit 
assessments will be combined with the assessments for the first visit in SHP633-307; thereafter 
clinic visits will occur every 3 months (Table 2). 
Subjects enrolling from TED-C14-004 will have blood samples taken for teduglutide 
pharmacokinetic (PK) analysis at predose and at 15, 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 
12 hours post dose at the first visit that they enter in this study. Subjects enrolling from 
SHP633-306 will have blood samples taken for teduglutide PK analysis at predose and 1 and 
2 hours post dose at the first clinic visit in this study. 
3.2
Duration and Study Completion Definition
The study will continue until teduglutide is commercially available, the subject’s participation in 
this study is discontinued, or the study is discontinued. The subject’s maximum duration of 
participation is expected to be approximately 3 years. A subject will be considered as having 
completed the study if the subject has not withdrawn early from the study for any reason prior to 
completing the end of study (EOS) visit.
If teduglutide is approved for marketing, this study will be continued as a post-marketing study. 
This protocol will continuously be used. “Clinical Study” mentioned in the protocol will be read 
as “Post-marketing Study” as appropriate.
3.3
Sites and Regions
This study is planned to be conducted in approximately 5 sites in Japan.
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4
STUDY POPULATION
Approximately 5 subjects who completed Study SHP633-306 and up to 7 subjects in 
TED-C14-004 may enroll in this extension study.
4.1
Inclusion Criteria
Subjects who meet all of the following criteria will be enrolled in this study:
1. Ability to voluntarily provide written, signed, and informed consent to participate in the
study.
2. Completion of the SHP633-306 study or participation in TED-C14-004 Stage 3 or
Stage 4.
3. Females of childbearing potential must agree to comply with the contraceptive
requirements of the protocol.
4. An understanding, ability, and willingness to fully comply with study procedures and
restrictions.
4.2
Exclusion Criteria
There are no exclusion criteria for this study.
4.3
Reproductive Potential 
To be eligible for treatment with teduglutide, sexually active females of childbearing potential 
must use a medically acceptable form of contraception. Females of childbearing potential must 
be advised to use medically acceptable contraceptives throughout the study period and for 
30 days following the last dose of investigational product. If hormonal contraceptives are used, 
they should be administered according to the package insert. Females of childbearing potential 
who are not currently sexually active must agree to use medically acceptable contraception if 
they become sexually active during the period of the study and for 30 days following the last 
dose of investigational product.
Females of childbearing potential must have a negative urine β-HCG pregnancy test at all visits 
where it is tested to participate in the study (see Section 8.1.6 for information about reporting a 
pregnancy). 
Females of childbearing potential must agree to use medically acceptable methods of 
contraception at all times during the study and for 30 days following the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
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discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
EOT/ET are to be performed as completely as possible. Comments (spontaneous or elicited) or 
complaints pertaining to study drug discontinuation made by the subject must be recorded in the 
source documents. The reason for termination, date of stopping investigational product, and the 
total amount of investigational product taken must be recorded in the electronic case report form 
(eCRF) and source documents. Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Study terminated by sponsor

Withdrawal by subject

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5
CONCOMITANT TREATMENT
5.1
Concomitant Treatment
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), study drug, 
and PN/IV must be recorded from the first visit and for the duration of the study in the 
appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF. Short 
term prescriptions lasting less than 72 hours should be recorded in the clinical database as 
concomitant medications, not as PN/IV adjustments. Examples include fluid resuscitation during 
treatment of sepsis or acute gastroenteritis, and modification of PN/IV due to interruption of 
central venous access (PN/IV prescription changes that last 72 hours or more should be recorded 
in the clinical database as PN/IV adjustments - examples include recurrent replacement of fluid 
losses, titration of PN/IV due to changes in intestinal absorptive function, and discontinuation of 
PN/IV due to achievement of enteral autonomy).
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Titration of concomitant enteral medications should be 
considered when drugs, especially those with a narrow therapeutic index, are given.
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the first visit (Table 3):
Table 3
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the First Visit
Glucagon-like peptide-2, human growth hormone, or analogs of these 
hormones
6 months
Octreotide, dipeptidyl peptidase 4 inhibitors, GLP-1 analogs, and enteral 
glutaminea
30 days
a Enteral glutamine refers to L-glutamine powder for oral solution, such as Nutrestore® or Endari™, administered in quantities of 
5 g or more per dose or more than 10 g per day. The use of elemental formulas that contain glutamine, such as Elental®, is 
allowed.
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg teduglutide as a white lyophilized powder to be reconstituted before use with 
0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each vial of 
teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and 
dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment
All subjects will receive teduglutide 0.05 mg/kg once daily.
6.2.2
Dosing 
Teduglutide 0.05 mg/kg once daily will be administered daily by subcutaneous (SC) injection 
into either thigh or arm or 1 of the 4 quadrants of the abdomen (in subjects without a stoma). 
Each day, the injection site should be rotated. For subjects with a stoma, the quadrant of the 
abdomen containing the stoma should not be used. The subject should be dosed at approximately 
the same time each day. Consecutive doses should be separated by at least 12 hours. The dose of 
study drug administered at time of entry may be adjusted based on change in the subject’s weight 
from baseline of the core study (SHP633-306 or TED-C14-004). Detailed instructions for 
reconstitution and injection of the investigational product can be found in the Instructions for 
Use.
Any subject who achieves complete independence from PN/IV support at any time during the 
treatment period will continue to receive teduglutide treatment. 
6.2.2.1
Subject Administration
The first dose of teduglutide will be administered by a study physician. The processes for 
training the subject to self-administer teduglutide and for providing oversight of study drug 
administration are described in the Site Training Guide. Before a subject is permitted to 
administer teduglutide, the study physician must observe the subject administering the study 
drug at least twice in compliance with the teduglutide administration checklist. The checklist is 
included as an appendix to the Site Training Guide. 
After the study physician certifies that the subject can safely administer the study drug, 
subsequent doses may be administered by the subject at home without direct supervision by the 
physician. However, at selected study visits during the dosing period (refer to Table 1 for subject 
enrolling from SHP633-306 and Table 2 for subjects enrolling from TED-C14-004), 
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administration of the study drug must be performed under direct supervision by the study 
physician, and the teduglutide administration checklist must be completed again. This ensures 
that the subject continues to administer the study drug correctly and safely throughout the dosing 
period.
If at any time a study physician suspects that the subject is no longer capable of administering 
the study drug safely and accurately, the subject should be reassessed by a study physician using 
the teduglutide administration checklist. If the subject is deemed unable to administer the study 
drug, dosing must be performed by a study physician until the subject is retrained and 
proficiency is confirmed using the teduglutide administration checklist. 
Eligibility for teduglutide to be administered by a subject will be judged by a study physician 
using the following criteria. Refer to the checklist included as an appendix to the Site Training 
Guide.
Criteria to Initiate Teduglutide Administration by the Subject:

The subject’s condition is stable.

The subject has been sufficiently trained and is able to administer teduglutide in
compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Subject:

The subject is unable to administer teduglutide in compliance with the checklist.

The subject’s condition has deteriorated such that the study physician assesses it is
inappropriate for the subject to have teduglutide self-administered. In addition to
discontinuing administration of teduglutide by the subject, if a subject sustains an adverse
drug reaction where the symptoms are considered intolerable, dose interruption or study
drug discontinuation should be considered.

In the study physician’s judgment, it is inappropriate for the subject to continue
administration of the study drug for any other reason.
6.2.3
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling and Packaging
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
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All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product and ancillary kits will be stored refrigerated at a temperature 
between 2°C and 8°C (35.6°F to 46.4°F) until dispensed to a subject. The prefilled sterile water 
for injection syringes will be stored at a temperature between 2°C to 25°C. Once 
dispensed/supplied to a subject, the investigational product can be stored refrigerated or up to a 
controlled room temperature (acceptable range of 2°C to 25°C, or 35.6°F to77°F). The subject 
will be instructed to keep the investigational product and sterile water diluent at controlled room 
temperature. If there are concerns that the controlled room temperature cannot be maintained, the 
investigational product may be refrigerated. The study drug is for single use only, and should be 
used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product and ancillary kits are maintained within an established temperature range. The 
investigator is responsible for ensuring that the temperature is monitored throughout the duration 
of the study and that records are maintained; the temperature should be monitored continuously 
by using either an in-house system, a mechanical recording device such as a calibrated chart 
recorder, or by manual means, such that both minimum and maximum thermometric values over 
a specific time period can be recorded and retrieved as required. Such a device (ie, certified 
min/max thermometer) would require manual resetting upon each recording. The sponsor must 
be notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The sponsor 
will determine the ultimate impact of excursions on the investigational product and will provide 
supportive documentation as necessary. Under no circumstances should the product be dispensed 
to subjects until the impact has been determined and the product is deemed appropriate for use 
by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
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6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
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Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the pharmacy manual for additional information.
6.5
Subject Compliance
The subjects must be instructed to bring unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability must be assessed and 
recorded at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual 
count level for opened containers/packaging.
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject if he/she has administered the investigational product according to 
instructions. If any doses have been missed, the reason for missed dose should be documented in 
the subject’s source documentation including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and adverse events (AEs), a lapse in investigational product 
delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol. 
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7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. The next scheduled visit should be based on the 
previous visit, not on Visit 1.
Subjects who drop out of the study prior to the final visit should have all early termination 
procedures done whenever possible.
7.1.1
First Visit
The last visit for SHP633-306/TED-C14-004 may be combined with the first visit for 
SHP633-307. 
Prior to performing any study-related procedures (including those related to Visit 1), the 
investigator or his/her designee must obtain written informed consent from the subject. The 
Visit 1 assessments and procedures, beginning with informed consent, will be performed as 
outlined in Table 1 for subjects transitioning from SHP633-306 and in Table 2 for subjects 
transitioning from TED-C14-004. 
7.1.2
Treatment Period
The treatment period will be performed as outlined in Table 1 and Table 2.
For subjects transitioning from SHP633-306, clinic and phone visits will then alternate on a 
monthly basis through Month 24; thereafter, clinic visits will occur every 3 months (Table 1). 
For subjects transitioning from TED-C14-004, clinic visits will occur every 3 months (Table 2).
The study will continue until teduglutide is commercially available, the subject’s participation in 
this study is discontinued, or the study is discontinued. 
7.2
Study Evaluations and Procedures
7.2.1
Efficacy Assessments
7.2.1.1
Subject Diaries
Diaries will be provided to subjects. Subjects will record their PN/IV support for 2 weeks prior 
to each scheduled clinic and interim safety visit. Prior to each scheduled clinic visit and interim 
safety visit, subjects will also record all enteral fluid intake and urine output over a 48-hour 
period. Diaries will be distributed to subjects at the time of informed consent and at clinic visits 
according to the study schedules. Diaries may be completed by the subject or the subject's 
designee if the subject is physically unable to enter data on his/her own.
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7.2.1.2
Prescribed Parenteral Nutrition 
Adjustments to PN/IV should be based on the guidelines 
 At the interim visits the 
PN/IV will be changed if the previous adjustment was not tolerated. Physician-directed changes 
in a subject’s PN/IV volume must be followed by an interim safety visit 5 to 7 days after the 
adjustment is implemented. If the subject has a AE that prevents him/her from adhering to study 
requirements, including the PN/IV adjustment algorithm, the subject may be withdrawn from the 
study.
The prescribed PN/IV weekly total volume and days per week will be recorded. Changes in 
parenteral support prescription that reflect changes in the subject's intestinal absorption are 
recorded. Temporary adjustments to parenteral nutrition or IV fluids that last less than 72 hours 
may be recorded at the discretion of the investigator, but all parenteral support prescriptions that 
last more than 72 hours must be recorded. The PN/IV constituents are at the discretion of the 
prescribing physician the identities of parenteral support constituents do not recorded. 
7.2.1.3
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass. If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line. The 
samples will be processed according to instructions in the laboratory manual.
7.2.2
Safety Assessments
7.2.2.1
Laboratory Evaluations
Safety laboratory tests are to be performed at site visits with results processed by a central 
laboratory. Although subjects do not need to be in a fasted state at the time of their clinic visit, 
they should avoid large meals or large volumes of fluid, including PN/IV with lipids, within 
3 hours of the clinic visit to permit consistent assessment.
Safety lab tests performed at interim safety visits after PN/IV adjustments will consist of 
hemoglobin, hematocrit, serum blood urea nitrogen, creatinine, and urine sodium, and may be 
performed at the investigational site laboratory.
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved. New clinically significant lab tests results should be 
reported as AEs (see Section 8).
Tests include the following (Table 4):
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Table 4
List of Laboratory Tests
Hematology:

Hematocrit

Hemoglobin

Platelet count

Red blood cell count

Red blood cell morphology, if needed

White blood cell count with differential
Urinalysis: 

Blood

Glucose

Leucocytes

Microscopic analysis

pH

Protein

Specific gravity

Urine Sodium
Pregnancy tests (females of childbearing potential):

Urine β-HCG
Biochemistry:

Albumin

Alkaline phosphatase

Alanine aminotransferase

Amylase

Aspartate aminotransferase

Bilirubin (total , direct, and indirect)

Blood urea nitrogen

Calcium (total)

Chloride

Cholesterol

Citrulline (plasma)

C-reactive protein

Creatinine

Creatinine clearance

Gamma-glutamyl transferase

Glucose

Lipase

Magnesium

Phosphorus

Potassium

Sodium

Triglycerides

Uric acid
7.2.2.2
Antibodies to Teduglutide 
Blood samples for analyses of antibodies to teduglutide will be collected. Samples must be 
drawn at least 14 hours after dosing. 
Anti-teduglutide antibody testing is a 3-step process. If a sample tests negative, no further testing 
is done. If a sample tests positive, further testing is done for teduglutide-specific antibodies. If 
teduglutide-specific antibodies are detected, the test is deemed “positive” and the titer derived, 
and neutralizing antibody testing is done. Subjects who test positive for teduglutide-specific 
antibodies may remain on treatment and blood samples for antibody testing will continue to be 
collected as per protocol schedule (Table 1 and Table 2). 
Blood samples for anti-teduglutide antibody testing may be stored and then analyzed together 
periodically to streamline the testing procedure. However, if an investigator suspects that a 
subject is experiencing an AE that may be associated with the development of anti-drug 
antibodies, relevant samples will be tested for the presence of anti-drug antibodies upon request. 
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7.2.2.3
Physical Examinations
Physical examinations will be performed according to the study schedules to assess the subject’s 
physical status. New clinically significant abnormalities that are detected or diagnosed after 
study evaluations have begun (after signing of the informed consent) should be recorded on the 
appropriate AE page of the eCRF. Full physical examination to be performed at first and last 
visits and on an annual basis; a focused examination will be performed at all other study visits.
7.2.2.4
Vital Signs, Body Weight, and Height
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse rate, body temperature (°C), and height at
first visit for all subjects. Blood pressure should be determined by cuff (using the same method, 
the same arm, and in the same position throughout the study). Subjects should be weighed on the 
same scale at each study visit. New clinically significant vital sign abnormalities should be 
recorded on the appropriate AE page of the eCRF.
7.2.2.5
Electrocardiograms
A 12-lead ECG will be performed at the study center after the subject has been resting for at least 
5 minutes. Results will include general findings only (normal, abnormal-not clinically 
significant, abnormal-clinically significant). If abnormal, the nature of the abnormality will be 
collected. Investigators are responsible for providing their own interpretation of the ECG and this 
will be captured on the eCRF. 
Electrocardiogram tracings should be printed, signed, and dated by the investigator, and kept 
with the subject’s source documents.
7.2.2.6
Gastrointestinal-specific Testing
COLONOSCOPY/SIGMOIDOSCOPY
For subjects who enter the study from SHP633-306, a colonoscopy/sigmoidoscopy of the 
remnant colon with polyp removal will be conducted at Visit 1, Visit 25 and EOS/ET. For 
subjects who enter the study from TED-C14-004, colonoscopy/sigmoidoscopy will be performed 
at V1 and at EOS/ET. The date and result of colonoscopy are to be recorded in the eCRF.
ESOPHAGOGASTRODUODENOSCOPY
For subjects who enter the study from TED-C14-004, EGD is required at the first clinic visit of 
SHP633-307. For these subjects, EGD is also required at EOS/ET for subject who present any of 
the gastric cancer risk factors listed below. 
For subjects who enter from SHP633-306, EGD is required at V1,V25, and EOS/ET for subjects 
who have any of the gastric cancer risk factors listed below.
The gastric cancer risk factors are listed below:  

Age 40 or over at the time of the clinic visit

History of H pylori gastritis
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
History of atrophic gastritis

History of intestinal metaplasia or dysplasia in the stomach
The dates and results of all EGDs are to be recorded in the eCRF.
7.2.2.7
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 study visits as required. The center staff will contact the subject 
at least 48 hours before the scheduled visits to remind the subject to start measuring I/O, and to 
record these measurements into the diary. At these times of 48-hour measurements, the subject 
should maintain their usual oral fluid intake. These measurements will also be collected at all 
interim safety visits.
7.2.3
Pharmacokinetic Assessments
Subjects enrolling from SHP633-306 will have blood samples taken for teduglutide PK analysis 
at the first clinic visit (Visit 1)in this study:

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least
14 hours after the previous dose

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes
Subjects enrolling from TED-C14-004 will have blood samples taken for teduglutide PK analysis 
at the first visit (Visit 1) that they enter in this study:

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least
14 hours after the previous dose

15 minutes postdose: ±5 minutes

30 minutes postdose: ±5 minutes

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes

3 hours postdose: ±10 minutes

4 hours postdose: ±30 minutes

6 hours postdose: ±30 minutes

8 hours postdose: ±30 minutes

10 hours postdose: ±30 minutes

12 hours postdose: ±30 minutes
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Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a central 
line. The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) and 
the person administering teduglutide (subject or physician) must be specified. 
If a subject is unable to provide blood samples for PK at the first clinic visit (Visit 1), PK 
samples can be collected up to 5 days after Visit 1.
7.3
Changes to Study Procedures Due to a Pandemic
The following information provides guidance regarding changes to the study procedures that 
could be implemented for study participants or study sites that are impacted by a pandemic (eg, 
coronavirus disease 2019 [COVID-19] or other future similar unexpected public health concerns) 
that require physical distancing that may result in subjects missing their visits. This guidance 
takes references from the FDA Guidance on Conduct of Clinical Trials of Medical Products 
during COVID-19 Public Health Emergency Guidance for Industry, Investigators, and 
Institutional Review Boards, March 2020 and updated on 02 July 2020, the European Medicines 
Agency (EMA) Guidance on the Management of Clinical Trials During the COVID 19 
(Coronavirus) Pandemic, Version 3 (28 April 2020), and the EMA Points to consider on 
implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical 
trials, dated 26 June 2020.
Because a pandemic (eg, COVID-19) may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case-by-case basis by the principal investigator, in 
consultation with the study team (and the medical team as needed), while maintaining patient 
safety and confidentiality as the priority.
Procedural changes due to COVID-19 (or other similar pandemic) may include the following:

Informed Consent Form Procedure: If necessary, informed re-consent from a current study
participant may be obtained via electronic informed consent capabilities, or an electronic
face-to-face consent interview when these individuals are unable to travel to the site, based
on local regulations or requirements.

Clinic / Telephone Visits:   In situations where a clinic visit is not completed due to a
COVID-19 (or other similar pandemic) concern, a telephone visit may be conducted as an
unscheduled safety assessment on subject well-being. The on-site visit will be recorded as
“Not Done” with a free text comment referencing COVID-19 (or similar pandemic) and
the telephone visit will be documented in the study records and recorded as an unscheduled
visit in the eCRF, with a free text comment indicating “Telephone visit”.

Deviations from protocol-specified procedures, eg, missing visits, missing data, alternative
visits, etc. will be recorded as related to a pandemic (eg, COVID-19 or other similar
pandemic).

Secure direct-to-patient delivery of the study drug from the investigational site to subjects
may be implemented, as per investigational site and sponsor agreement.
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
In the event a monitor cannot visit the site in a timely manner due to the COVID-19
pandemic or other similar pandemic, alternative monitoring approaches such as remote
source data verification or telephone contact may be used to maintain patient safety and
ensure data quality and integrity. Alternative monitoring approaches should be used only
where allowed by applicable local regulations and permitted by the IRB/IEC.
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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.2. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
Adverse events that are related to investigational product that are not resolved at 
end-of-treatment (EOT) will be followed until the event resolves or stabilizes, as judged by 
the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during treatment with investigational product, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value. When evaluating such changes, the extent of deviation from the reference range, 
the duration until return to the reference range, either while continuing treatment or after the 
EOT with the investigational product, and the range of variation of the respective parameter 
within its reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the pretreatment value observed closest to the start of treatment with teduglutide, 
further investigations should be done until the values return to within the reference range or until 
a plausible explanation (eg, concomitant disease) is established for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value or vital sign is clinically significant and 
therefore may represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.2.
Any report of pregnancy for any female study participant or female partner of male study 
participant must be reported within 24 hours to IQVIA Services Japan K.K. using the Shire 
Investigational and Marketed Products Pregnancy Report Form. In the event a subject becomes 
pregnant during the study, teduglutide administration must be immediately and permanently 
discontinued.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant using the Shire Investigational and Marketed Products Pregnancy Report 
Form. It is the responsibility of the investigator to obtain this information within 30 calendar 
days after the initial notification, and approximately 30 calendar days and 1 year postpartum, and 
report to IQVIA Services Japan K.K.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered serious adverse events (SAEs) and must be reported using the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events and Non-serious AEs as Required by 
Protocol. Note: An elective abortion is not considered an SAE.
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In addition to the above, if the investigator determines that complications of the pregnancy meet 
serious criteria, it must be reported as an SAE using the Shire Clinical Study Adverse Event 
Form for SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational 
and Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
using the SAE reporting form whether or not they result in an AE/SAE as described in 
Section 8.2, but such events are only recorded in the eCRF if they result in an AE. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or
medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at any
dose (Note: this includes a situation where the investigational product is not used as directed
at the dose prescribed by the protocol).

Overdose – Administration of the investigational product at a dose or frequency greater than
0.05 mg/kg subcutaneous once daily. An overdose occurs if any of the following criteria are
met:

More than 0.05 mg/kg is given at any one time

Consecutive doses are spaced less than 12 hours apart

Any more than 0.05 mg/kg in one day (a day is defined as beginning at 12:00 AM and
ending at 11:59 PM)

Medication Error – An error made in prescribing, dispensing, administration, and/or use of an
investigational product. For studies, medication errors are reportable to the sponsor only as
defined below.

Cases of subjects missing doses of the investigational product are not considered
reportable as medication errors.

Medication errors should be collected/reported for all products under investigation.

The administration and/or use of an expired investigational product should be considered
as a reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the sponsor or 
designee within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the sponsor or designee within 24 hours of the first awareness of the event even if 
the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol and verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested). The investigator must fax or 
e-mail the completed form to IQVIA Services Japan K.K. Applicable fax numbers and email
addresses are found in the Emergency Contact Information.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an
event in which the subject was at risk of death at the time of the event; it does not refer to an
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note:
Hospitalizations, which are the result of elective or previously scheduled surgery for
preexisting conditions, which have not worsened after initiation of treatment, should not be
classified as SAEs. For example, an admission for a previously scheduled ventral hernia
repair would not be classified as an SAE; however, complication(s) resulting from a
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death,
be life-threatening, or require hospitalization may be considered an SAE when, based upon
appropriate medical judgment, they may jeopardize the subject and may require medical or
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surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed consent is 
obtained until the defined follow-up period stated in Section 7.1.2, and must be reported to the 
sponsor or designee within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the sponsor or 
designee within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities of related, unexpected 
SAEs. 
In addition, the sponsor and/or designee is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the teduglutide program.
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The investigator is responsible for notifying the local Institutional Review Board (IRB) or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of preexisting polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to
those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor or designee must be informed within 24 hours of first 
awareness as per the SAE notification instructions described in Section 8.2.2 even if the event 
does not fulfill seriousness criterion.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is enrolled, it is expected that site personnel 
will complete the eCRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The data collected in this study will be analyzed by the sponsor or designee. All statistical 
analyses will be performed using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. 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. The derivations of the weekly PS volume will be described 
in the study statistical analysis plan in detail.
9.4
Planned Interim Analysis 
An interim analysis will be conducted when the last subject who enters the study from 
SHP633-306 reaches the Month 6 visit (Visit 7) and the last subject from TED-C14-004 reaches 
Visit 1. Additional interim analyses may be conducted during the study, as needed. 
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Analyses will be descriptive in nature. No formal comparisons are planned and no hypotheses 
will be formally tested. Due to the open-label nature of this study, personnel involved in 
conducting the interim analyses will have access to treatment assignments. 
9.5
Sample Size Calculation and Power Considerations
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core study SHP633-306 and TED-C14-004. Approximately 5 subjects 
who completed Study SHP633-306 and 7 subjects in the extension phase of TED-C14-004 may 
enroll in this extension study. 
9.6
Study Population
The safety population will include all enrolled subjects in the study. A subject will be considered 
enrolled in the study once the informed consent has been obtained and the subject meets all of 
the study inclusion criteria. Safety population will be used for both safety and efficacy analyses. 
The pharmacokinetic population will include all subjects who receive at least 1 dose of 
teduglutide and have at least 1 evaluable post-dose pharmacokinetic concentration value. 
9.7
Efficacy Analyses
The following efficacy endpoints will be analyzed at each study visit and at the EOS, relative to 
the baseline of the core studies (SHP633-306 and TED-C14-004):

Reduction in PN/IV volume of at least 20%

Absolute and relative change in PN/IV volume

Complete weaning off PN/IV

Change in days per week of PN/IV

Change in plasma citrulline
The absolute and percent change in weekly PN/IV volume, days per week of PN/IV support, and 
plasma citrulline from baseline to each scheduled visit, as well as at EOS, will be summarized 
using descriptive statistics. The number and percentage of subjects who demonstrate reduction in 
PN/IV volume of 20% will also be summarized.
The number and percentage of subjects who completely wean off PN/IV support by EOS will be 
summarized. A subject will be considered to have achieved from PN/IV (completely weaned off 
PN/IV) if the investigator prescribes no PN/IV at EOS and there is no use of PN/IV recorded in 
the subject diary during the 2 weeks prior to the last dosing visit. 
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9.8
Safety Analyses
The safety endpoints include AEs, 12-lead ECG, vital signs, laboratory safety data, antibodies to 
teduglutide, and 48-hour urine output, body weight, BMI and gastrointestinal-specific tests.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
dictionary. Treatment-emergent AEs are defined as AEs that started or worsened on or after the 
date and time of the first dose of study dose. Treatment-emergent AEs will be summarized by 
system organ class and preferred term using descriptive statistics (eg, number and percentage of 
subjects). Adverse events will be summarized by severity, relationship to treatment, and for AEs 
of special interest, AEs leading to discontinuation, and AEs leading to death. Serious AEs will 
also be tabulated by overall and treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, BMI, ECG variables, and
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, 
the number and percentage of subjects in specified categories) will be used to summarize the 
absolute values and change from baseline at each time point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Pharmacokinetics Analyses
Teduglutide plasma concentrations will be summarized using pharmacokinetic population with 
descriptive statistics (number, mean and standard deviation, minimum, median, and maximum) 
at nominal time points. 
The following PK parameters will be derived as appropriate (for subjects with rich PK sample 
collection): area under the plasma concentration-time curve from zero to the last measurable 
concentration (AUC0–t); maximum plasma concentration (Cmax); time to Cmax (tmax); 
terminal-phase half-life (t1/2); apparent clearance (CL/F); and apparent volume of distribution 
(V/F) and summarized using descriptive statistics (number, mean, standard deviation, geometric 
mean, and CV%, minimum, median, and maximum).
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10
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, contract research organization [CRO]) 
used in this study will be maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied, as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
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the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
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10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designe and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log. All data will have 
separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. The study monitor will verify 
the contents against the source data per the monitoring plan. If the data are unclear or 
contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, original clinical laboratory reports, and imaging reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the subject agrees 
to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays etc). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
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10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
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Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. 
The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices) when forming a publication steering committee, which is done for 
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large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. 
If requested in writing by Shire, the institution and principal investigator shall withhold 
submission of such publication for up to an additional 60 days to allow for filing of a patent 
application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11
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