Clinical trial NCT04465396
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Shire
Start date: 2021-01-13; Completion date: 2021-08-20
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the bioavailability of teduglutide administered as a single subcutaneous (SC) fixed dose (depending upon participant weightband assignment) delivered by a syringe injection and the same fixed dose delivered by the pen injector in healthy participants.

Detailed description:
This is a 2-period crossover study and consists of two cohorts. Cohort 1 consists of participant's with greater than or equal to (\>=) 40.0 kilogram (kg) to lesser than or equal to (\<=) 75.0 kg of weight and Cohort 2 consists of participant's with greater than (\>) 75.0 kg to \<= 120.0 kg of weight. Participants in each cohort will be randomized to 1 of 2 treatment sequences AB or BA. Randomization will be stratified by injection site (i.e., thigh, abdomen, and arm) within each cohort.

Arms: arm 1: Teduglutide, 3 mg, subcutaneous (SC) injection using a syringe, once on Day 1 of Treatment Period 1 (Treatment A1), followed by same dose SC pen injector, once on Day 1 of Treatment Period 2 (Treatment B1). A Washout Period of 7 days was maintained between Treatment Periods 1 and 2. Participants with \>=40.0 kg to \<=75.0 kg of weight were included in Cohort 1. arm 2: Teduglutide, 3 mg, SC pen injector, once on Day 1 of Treatment Period 1 (Treatment B1), followed by same dose SC injection using a syringe, once on Day 1 of Treatment Period 2 (Treatment A1). A Washout Period of 7 days was maintained between the Treatment Periods 1 and 2. Participants with \>=40.0 kg to \<=75.0 kg of weight were included in Cohort 1. arm 3: Teduglutide, 4 mg, SC injection using a syringe, once on Day 1 of Treatment Period 1 (Treatment A2), followed by same dose SC pen injector, once on Day 1 of Treatment Period 2 (Treatment B2). A Washout Period of 7 days was maintained between Treatment Periods 1 and 2. Participants \>75.0 kg to \<=120.0 kg of weight were included in Cohort 2. arm 4: Teduglutide, 4 mg, SC pen injector, once on Day 1 of Treatment Period 1 (Treatment B2), followed by same dose SC injection using a syringe, once on Day 1 of Treatment Period 2 (Treatment A2). A Washout Period of 7 days was maintained between Treatment Periods 1 and 2. Participants \>75.0 kg to \<=120.0 kg of weight were included in Cohort 2.
Interventions: intervention 1: Teduglutide intervention 2: Syringe Injection intervention 3: Pen injector
Intervention descriptions: intervention 1: Participants received 3 mg or 4 mg of Teduglutide SC syringe injection followed by pen injector or vice versa depending upon the treatment sequence AB or BA on Day 1 of Treatment Periods 1 and 2. intervention 2: Teduglutide was administered using syringe. intervention 3: Teduglutide was administered using pen injector.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
NCT Number: 
NCT04465396
Study Title: 
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, 
Crossover Study to Evaluate the Bioavailability of Teduglutide Administered 
Subcutaneously by Syringe Injection Versus Pen Injector in Healthy Adult 
Subjects
Study Number: 
TAK-633-1001
Protocol Version and Date: 
Amendment 03:
09 Dec 2020
For non-commercial use only


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, Crossover Study to 
Evaluate the Bioavailability of Teduglutide Administered Subcutaneously by Syringe 
Injection Versus Pen Injector in Healthy Adult Subjects
Study Identifier:
TAK-633-1001 
Compound:
Teduglutide
Date:
09 Dec 2020
Version/Amendment 
Number:
Amendment 03
Amendment History: 
Date
Amendment Number
Amendment Type
Region
28 Feb 2020
Initial Version
United States
29 Apr 2020
01
Not Applicable
United States
28 Sep 2020
02
Not Applicable
United States
09 Dec 2020
03
Not Applicable
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 2
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................................6
LIST OF APPENDICES..................................................................................................................6
1.
STUDY SUMMARY ...............................................................................................................7
2.
STUDY SCHEMATIC...........................................................................................................12
3.
SCHEDULE OF STUDY PROCEDURES............................................................................13
4.
INTRODUCTION..................................................................................................................16
4.1
Background ..............................................................................................................16
4.2
Rationale for the Proposed Study.............................................................................17
4.3
Benefit/Risk Profile..................................................................................................18
5.
STUDY OBJECTIVES AND ENDPOINTS..........................................................................19
5.1
Hypothesis................................................................................................................19
5.2
Study Objectives ......................................................................................................19
5.2.1
Study Primary Objective........................................................................................19
5.2.2
Study Secondary Objectives ..................................................................................19
5.3
Endpoints..................................................................................................................19
5.3.1
Primary Endpoints .................................................................................................19
5.3.2
Secondary Endpoints .............................................................................................20
6.
STUDY DESIGN AND DESCRIPTION...............................................................................21
6.1
Study Design ............................................................................................................21
6.2
Dose Escalation........................................................................................................22
6.3
Rationale for Study Design, Dose, and Endpoints...................................................22
6.3.1
Rationale of Study Design .....................................................................................22
6.3.2
Rationale for Dose .................................................................................................22
6.3.3
Rationale for Endpoints .........................................................................................22
6.3.3.1
Pharmacokinetic Endpoints....................................................................22
6.3.3.2
Safety, Tolerability, and Performance Endpoints ..................................23
6.3.4
Future Biomedical Research..................................................................................23
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures................23
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters ................................................................................................................23
6.5
Study Beginning and End/Completion.....................................................................23
6.5.1
Definition of Beginning of the Study.....................................................................23
6.5.2
Definition of End of the Study...............................................................................23
6.5.3
Definition of Study Completion.............................................................................23
6.5.4
Definition of Study Discontinuation......................................................................24
For non-commercial use only


Takeda
CONFIDENTIAL
Page 3
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
6.5.5
Criteria for Premature Termination or Suspension of the Study ...........................24
6.5.6
Criteria for Premature Termination or Suspension of a Site..................................24
7.
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS....................25
7.1
Inclusion Criteria......................................................................................................25
7.2
Exclusion Criteria.....................................................................................................25
7.3
Excluded Medications, Supplements, Dietary Products ..........................................27
7.4
Diet, Fluid, Activity .................................................................................................27
7.4.1
Diet and Fluid ........................................................................................................27
7.4.2
Activity ..................................................................................................................28
7.5
Criteria for Discontinuation or Withdrawal of a Subject .........................................28
7.6
Procedures for Discontinuation or Withdrawal of a Subject....................................28
7.7
Subject Replacement................................................................................................28
8.
CLINICAL STUDY MATERIAL MANAGEMENT............................................................29
8.1
Clinical Study Drug..................................................................................................29
8.1.1
Clinical Study Drug Labeling................................................................................29
8.1.2
Clinical Study Drug Inventory and Storage...........................................................29
8.1.3
Clinical Study Drug Blinding ................................................................................29
8.1.4
Randomization Code Creation and Storage...........................................................29
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure ....................................30
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.................................30
9.
STUDY PROCEDURES........................................................................................................31
9.1
Administrative Procedures .......................................................................................31
9.1.1
Informed Consent Procedure .................................................................................31
9.1.1.1
Assignment of Screening and Allocation Numbers ...............................31
9.1.1.2
Study Drug Assignment .........................................................................31
9.1.2
Inclusion and Exclusion.........................................................................................31
9.1.3
Medical History/Demography ...............................................................................31
9.1.4
Concomitant Medications......................................................................................31
9.2
Clinical Procedures and Assessments ......................................................................31
9.2.1
Full Physical Examination.....................................................................................32
9.2.2
Height and Weight .................................................................................................32
9.2.3
Body Mass Index (BMI)........................................................................................32
9.2.4
Vital Signs..............................................................................................................32
9.2.5
12-Lead ECG .........................................................................................................33
9.2.6
Injection Site Reaction and Injection Site Injury Assessments .............................33
9.2.7
Study Drug Administration....................................................................................33
9.2.8
AE Monitoring.......................................................................................................34
For non-commercial use only


Takeda
CONFIDENTIAL
Page 4
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
9.2.9
Laboratory Procedures and Assessments...............................................................34
9.2.9.1
Clinical Laboratory Tests.......................................................................34
9.3
PK Samples ..............................................................................................................35
9.3.1
PK Measurements ..................................................................................................36
9.3.2
Biomarker Measurements......................................................................................36
9.3.3
PGx Measurements................................................................................................36
9.3.4
Confinement...........................................................................................................37
10. ADVERSE EVENTS..............................................................................................................38
10.1
Definitions and Elements of AEs.............................................................................38
10.1.1 SAEs ......................................................................................................................40
10.1.2 Special Interest AEs...............................................................................................41
10.2
AE Procedures..........................................................................................................41
10.2.1 Assigning Severity/Intensity of AEs......................................................................41
10.2.2 Assigning Causality of AEs...................................................................................42
10.2.3 Start Date ...............................................................................................................42
10.2.4 End Date.................................................................................................................42
10.2.5 Pattern of Adverse Event (Frequency)...................................................................42
10.2.6 Action Taken With Study Treatment.....................................................................42
10.2.7 Collection and Reporting of AEs, SAEs, Special Interest AEs, and 
Abnormal Liver Function Tests.............................................................................43
10.2.7.1
Collection Period....................................................................................43
10.2.7.2
Reporting AEs........................................................................................43
10.2.7.3
Reporting SAEs......................................................................................44
10.2.7.4
Reporting Special Interest AEs ..............................................................45
10.2.7.5
Close Monitoring and Treatment Discontinuation for Potential 
Drug-Induced Liver Injury (DILI) .........................................................45
10.2.8 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....46
11. STATISTICAL METHODS...................................................................................................47
11.1
Statistical and Analytical Plans................................................................................47
11.1.1 Analysis Sets..........................................................................................................47
11.1.1.1
PK Set.....................................................................................................47
11.1.1.2
Safety Set................................................................................................47
11.1.2 Analysis of Demography and Other Baseline Characteristics...............................47
11.1.3 PK Analysis ...........................................................................................................47
11.1.4 Pharmacodynamic Analysis...................................................................................48
11.1.5 Safety Analysis ......................................................................................................48
11.2
Interim Analysis and Criteria for Early Termination...............................................48
11.3
Determination of Sample Size..................................................................................49
For non-commercial use only


Takeda
CONFIDENTIAL
Page 5
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
12. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................50
12.1
Study-Site Monitoring Visits ...................................................................................50
12.2
Protocol Deviations..................................................................................................50
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................50
13. ETHICAL ASPECTS OF THE STUDY................................................................................51
13.1
IRB and/or IEC Approval ........................................................................................51
13.2
Subject Information, Informed Consent, and Subject Authorization.......................52
13.3
Subject Confidentiality.............................................................................................53
13.4
Publication, Disclosure, and Clinical Study Registration Policy.............................53
13.4.1 Publication and Disclosure ....................................................................................53
13.4.2 Clinical Study Registration....................................................................................54
13.4.3 Clinical Study Results Disclosure..........................................................................54
13.5
Insurance and Compensation for Injury...................................................................54
14. ADMINISTRATIVE AND REFERENCE INFORMATION................................................55
14.1
Administrative Information......................................................................................55
14.1.1 Study Contact Information - SAE..........................................................................55
14.1.2 Study Contact Information – Product Quality Complaint .....................................55
14.1.3 INVESTIGATOR AGREEMENT.........................................................................56
14.1.4 Study-Related Responsibilities..............................................................................57
14.1.5 List of Abbreviations .............................................................................................57
15. DATA HANDLING AND RECORDKEEPING...................................................................59
15.1
CRFs (Electronic and Paper)....................................................................................59
15.2
Record Retention......................................................................................................60
16. REFERENCES .......................................................................................................................61
For non-commercial use only


Takeda
CONFIDENTIAL
Page 6
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
LIST OF IN-TEXT TABLES
Table 1
Treatment Scheme for Each Cohort ................................................................7
Table 2
Treatment Scheme for Each Cohort ..............................................................21
Table 3
Excluded Medications, Supplements, and Dietary Products.........................27
Table 4
Primary Specimen Collections ......................................................................36
Table 5
Takeda Medically Significant AE List..........................................................41
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator ...............................................................62
Appendix B
Elements of the Subject Informed Consent...................................................64
Appendix C
Investigator Consent to the Use of Personal Information .............................67
Appendix D
Pregnancy and Contraception........................................................................68
Appendix E
Detailed Description of Amendments to Text...............................................71
For non-commercial use only


Takeda
CONFIDENTIAL
Page 7
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
1.
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Compound:
Teduglutide
Study Identifier (ID): TAK-633-1001
Phase: I
Protocol Title: A Randomized, Open-label, Two-treatment, Two-period, Single-dose, Crossover Study to 
Evaluate the Bioavailability of Teduglutide Administered Subcutaneously by Syringe Injection Versus Pen 
Injector in Healthy Adult Subjects
Study Design:
This is a randomized, open-label, two-treatment, two-period, two-sequence, single dose, crossover bioavailability 
study in healthy adult subjects. 
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first dosing. 
Subjects will be enrolled into 1 of 2 cohorts based on their weight (≥40.0 kg to ≤75.0 kg [Cohort 1] and >75.0 kg 
to ≤120.0 kg [Cohort 2]). In each cohort, subjects will be admitted to the clinical facility the day prior to each 
dosing and will be confined at least 24 hours; subjects will be released following completion of the 24-hour 
study procedures in each period. On Day 1 of Period 1, subjects in each cohort will be randomized to 1 of 
2 treatment sequences as indicated in Table 1 below. Fixed teduglutide doses (delivered by pen injector or from 
approved single-use vials) is 3 mg for subjects in Cohort 1 and 4 mg for subjects in Cohort 2. Each dose will be 
separated by a washout period of 7 days. Blood samples for teduglutide pharmacokinetics (PK) will be collected 
predose and for 24 hours following each teduglutide dose. 
Table 1
Treatment Scheme for Each Cohort
Weightband
Cohort/
Dose 
level
No. of 
Subjects
Sequence*
Treatment 
Period 1
(Day 1)
Washout 
Period
(7 days)
Treatment 
Period 2
Day 1)
≥40.0 kg - ≤75.0 kg
Cohort 1 
/ 3mg
n=16
AB
Reference
(fixed dose by 
vial and 
syringe)**
→
Test
(fixed dose by 
pen injector)**
>75.0 kg - ≤120.0 kg
Cohort 2 
/ 4mg
n=16
≥40.0 kg - ≤75.0 kg
Cohort 1 
/ 3mg
n=16
BA
Test
(fixed dose by 
pen injector)**
→
Reference
(fixed dose by 
vial and 
syringe)**
>75.0 kg - ≤120.0 kg
Cohort 2 
/ 4mg
n=16
* To ensure adequate distribution across 3 injection sites (ie, thigh, abdomen, and arm), randomization will be 
stratified by injection site within each cohort.
**Fixed teduglutide doses (delivered by pen injector or from approved single-use vials) is 3 mg for subjects in 
Cohort 1 (≥40.0 kg - ≤75.0 kg) and 4 mg for subjects in Cohort 2 (>75.0 kg - ≤120.0 kg).
Treatment A: Teduglutide administered by syringe injection 
Treatment B: Teduglutide administered by pen injector
Safety and tolerability will be assessed by treatment-emergent adverse events (TEAEs), including injection site 
reaction and injection site injury assessments, clinical laboratory evaluations, physical examinations, and vital 
signs.
All subjects who received at least one dose of study drug (including subjects who terminate the study early) will 
be contacted by the Clinical Research Unit (CRU) 7 (±2) days after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last study visit.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 8
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Study Primary Objective:
To evaluate the bioavailability of teduglutide following the administration of a single, subcutaneous (SC) fixed 
dose of 3 mg or 4 mg teduglutide (depending upon subjects assignment in one of two cohorts as defined by body 
weight) administered via manual injection or via pen injector in healthy subjects.
Study Secondary Objectives:
To evaluate the bioavailability of teduglutide, by injection site (ie, thigh, abdomen, and arm), following the 
administration of a single, SC fixed dose of 3 mg or 4 mg teduglutide (depending upon subjects assignment in 
one of two cohorts as defined by body weight) administered via manual injection or via pen injector in healthy 
subjects.
To evaluate other PK parameters of teduglutide, as appropriate, following the administration of a single dose of 
teduglutide administered via manual injection or pen injector in healthy subjects.
To assess the safety and tolerability of SC injections of teduglutide in healthy subjects.
To assess the safety and performance of the pen injector for SC drug administration in healthy subjects.
Study Subject Population: Healthy male and female subjects aged 18 – 45 years inclusive, at time of consent. 
Each subject in Cohort 1 will weigh ≥40.0 kg to ≤75.0 kg at screening and confirmed on Day -1 of Period 1 and 
each subject in Cohort 2 will weigh >75.0 kg to ≤120.0 kg at screening and confirmed on Day -1 of Period 1. 
Planned Number of Subjects:
The planned total sample size for this study is 
64 randomized subjects. 
Planned Number of Sites:
1
Dose Levels:
Cohort 1 (body weight ≥40.0 kg to ≤75.0 kg): 3 mg
Cohort 2 (body weight >75.0 kg to ≤120.0 kg): 4 mg
Route of Administration:
SC 
Duration of Treatment:
Single dose
Planned Study Duration:
Up to 6 weeks from screening to end of study (follow 
up)
Criteria for Inclusion:
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated informed consent and assent as applicable to 
participate in the study.
3.
Aged 18 - 45 inclusive at the time of consent. The date of signature of the informed consent is defined as 
the beginning of the screening period. This inclusion criterion will only be assessed at the first screening 
visit.
4.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential, refer to Appendix D.
5.
Considered “healthy” by the investigator. Healthy status is defined by absence of evidence of any active 
or chronic disease following a detailed medical and surgical history, a full physical examination including 
vital signs, 12-lead ECG, hematology, coagulation (as appropriate), serum chemistry, and urinalysis.
6.
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. Body weight for a subject in Cohort 1 will 
be ≥40.0 kg to ≤75.0 kg, and body weight for a subject in Cohort 2 will be >75.0 kg to ≤120.0 kg, 
inclusive. This inclusion criterion will be assessed at the screening visit and confirmed at first check-in.
Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric 
disease, gall bladder removal, or current or recurrent disease that could affect the action, absorption, or 
disposition of the investigational product, or clinical or laboratory assessments.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 9
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures. 
3.
Positive PCR (polymerase chain reaction) test for severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2), either with the absence or presence of the clinical symptoms of Coronavirus disease 2019 
(COVID-19).
4.
Known or suspected intolerance or hypersensitivity to teduglutide, closely-related compounds, or any of 
the stated ingredients.
5.
Significant illness, as judged by the investigator, within 2 weeks of the first dose of teduglutide.
6.
Known history of alcohol or other substance abuse within the last year prior to screening.
7.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first 
dose of teduglutide.
8.
Pregnant or lactating female.
9.
Within 30 days prior to the first dose of teduglutide:

Have used an investigational product (if elimination half-life is <6 days, otherwise 5 half-lives).

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s (or 
designee’s) opinion, may impact this study.

Have had any substantial changes in eating habits, as assessed by the investigator (or designee).
10.
Use of dipeptidyl peptidase 4 inhibitors within 30 days or 5 half-lives, whichever is greater, prior to 
administration of the first dose of teduglutide.
11.
Confirmed systolic blood pressure >140 mmHg or <90 mmHg, and diastolic blood pressure >90 mmHg 
or <40 mmHg at screening.
12.
Twelve (12)-lead ECG demonstrating QTcF >450 msec at screening. If the QTcF exceeds the 
aforementioned limits, the ECG should be repeated 2 more times and the average of the 3 QTcF values 
should be used to determine the subject’s eligibility.
13.
Positive screen for drugs of abuse or alcohol at screening and at each check-in.
14.
Male subjects who consume more than 21 units of alcohol per week or regularly consume more than 
3 units per day. Female subjects who consume more than 14 units of alcohol per week or regularly 
consume more than 2 units per day. (1 alcohol unit=150 mL of wine, or 360 mL of beer, or 45 mL of 45% 
alcohol).
15.
Positive HIV, HBsAg, or HCV antibody screen at screening.
16.
Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form 
(eg, gum, patch) based on subject self-reporting. Ex-users must report that they have stopped using 
tobacco for at least 3 months prior to receiving the first dose of teduglutide.
17.
Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine 
withdrawal headaches. One caffeine unit is contained in the following items: one 6 oz (180 mL) cup of 
coffee, two 12 oz (360 mL) cans of cola, one 12 oz (360 mL) cup of tea, three 1 oz (85 g) chocolate bars.
18.
Prior screen failure, randomization, participation, or enrollment in this study, or prior exposure to any 
GLP-2 analogs.
19.
Presence of lesions, rashes, tattoos, and moles etc. on administration sites not allowing adequate conduct 
of injection site reaction and injection site injury assessments.
20.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations; with the 
exception of occasional use of ibuprofen [1.2 g per 24 hour period] or acetaminophen [2 g per 24 hour 
period]). Current use is defined as use within 14 days of the first dose of teduglutide and throughout the 
study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 10
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Criteria for Evaluation and Analyses:
The primary endpoints of the study are the PK metrics* and will include: 

AUC0-tlast: Area under the concentration curve from time zero to the time of last measurable concentration 

Cmax: Maximum concentration 

AUC0-∞: Area under the concentration curve extrapolated to infinite time
*Beginning on Day 1 of each period, PK parameters will be calculated from reliable teduglutide 
concentration-time profiles using non-compartmental methods where all calculations will be based on actual 
sampling times.
The secondary endpoints will be assessed through evaluation of the following parameters: 
PK metrics* by injection site (ie, thigh, abdomen, and arm) including:

AUC0-tlast: Area under the concentration curve from time zero to the time of last measurable concentration 

Cmax: Maximum concentration

AUC0-∞: Area under the concentration curve extrapolated to infinite time
*Beginning on Day 1 of each period, PK parameters will be calculated from reliable teduglutide 
concentration-time profiles using non-compartmental methods where all calculations will be based on actual 
sampling times.

Other secondary PK parameters will include:
tmax: Time of first occurrence of Cmax
z: Terminal disposition phase rate constant
t1/2: Terminal disposition phase half-life
CL/F: Apparent total body clearance for extravascular administration divided by the fraction of dose 
absorbed
Vz/F: Apparent volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed

Occurrence of TEAEs, including injection site reactions and injection site injury assessments.

Routine clinical safety monitoring that includes: vital signs, clinical laboratory test results (hematology, 
serum chemistry, coagulation (as appropriate), and urinalysis) and physical examinations.

Occurrence of device malfunctions.
The safety endpoint and safety variables will be captured for both test and reference.
A list of potential device malfunctions will be provided to the study site as a reference list for data capture.
Statistical Considerations:
Statistical Methodology for Pharmacokinetic Endpoints
Statistical analysis of PK data will be based on the PK analysis data set. 
All individual concentration data and PK metrics will be listed for each subject and treatment together with 
summary statistics such as geometric mean, median, arithmetic mean, standard deviation (SD), coefficient of 
variation, geometric coefficient of variation, and minimum and maximum grouped by treatment and cohort. The 
time until first occurrence of Cmax is reached (tmax) will be also listed for each subject and treatment and 
summarized by medians, minimum and maximum grouped by treatment and cohort. The number of time points 
of the terminal log-linear phase used to estimate the terminal rate constant (z) and the residual area will be also 
provided for each subject and treatment. 
Individual concentration-time curves will be presented in linear/linear and log/linear scale. Figures showing the 
mean (with ±SD as error bars) as well as the median (with 25th to 75th quantiles as error bars) concentration time 
profiles grouped by treatment and cohort will be also presented in linear/linear and log/linear scale.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 11
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
The PK endpoints will also be analyzed by injection site (ie, thigh, abdomen, and arm).
PK metrics AUC0-tlast, AUC0-∞, and Cmax will be analyzed using an analysis of variance (ANOVA) model for 
each cohort separately. 
PK metrics will be transformed prior to analysis using a logarithmic transformation. The difference in means and 
the corresponding two-sided 90% confidence interval (CI) on the log-transformed scale will be obtained from 
that model. The difference in means and the corresponding CI will be back-transformed to obtain the ratio of 
geometric means and the corresponding two-sided 90% CI for the ratio on the original scale. The terms used in 
the ANOVA model will be sequence, subject within sequence, period, and treatment. According to EMA 
guideline (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr) (EMA 2010), subjects who will not provide evaluable data 
for both periods will be not included and fixed effects will be used for all terms.
To assess bioavailability between test and reference, the 90% CI for the ratio of geometric means for PK metrics, 
AUC0-tlast, AUC0-∞, and Cmax will be derived and compared (and would be contained within the acceptance 
interval of 80.00 to 125.00% if bioequivalent).
Statistical Methodology for Safety Endpoints:
Statistical analysis of safety data will be based on the safety analysis data set.
Safety data will be listed by subject and summarized by cohort and treatment using descriptive statistics. 
Continuous variables will be summarized by sample size, mean, SD, median, minimum, and maximum. 
Categorical variables will be summarized by number of subjects and the percent of subjects in each category.
TEAEs will be analyzed using the number and percentage of subjects reporting events, as well as the number of 
events, by system organ class and preferred term, severity, and causal relationship to the study treatment and 
device. Among TEAEs, injection site reactions and injection site injuries will be analyzed using the number and 
percentage of subjects reporting events, by preferred term, severity, and causal relationship to study treatment 
and device. Laboratory tests, vital signs, physical examinations, and corresponding changes from baseline will be 
summarized by study visit where baseline will be defined as the last non-missing assessment on or before Day 1 
prior to the first dose.
Device malfunctions will be listed for each subject and summarized by cohort using the number and percentage 
of events.
Sample Size Justification:
The overall power for the endpoints (AUC0-tlast, AUC0-∞, and Cmax) with a total sample size of 64 subjects will be 
92.6% power based on a 5% type 1 error and a Coefficient of Variation of 21%, assuming a true ratio of 
test/reference of 1.0 in their relative bio-availabilities based on the acceptance interval of 80.00 to 125.00%. The 
sample size of 28 subjects within each cohort (14 each sequence) was accounted for approximately 10% 
potential drop-outs and/or non-reliable concentration time-profiles to yield 32 subjects per cohort (16 subjects 
per sequence within each cohort). This sample size was calculated with SAS v9.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 12
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
2.
STUDY SCHEMATIC 
  
Screening
Treatment 
Period 1
(Day 1)
Treatment 
Period 2
(Day 1) 
Washout
Screening Period = Day -28 through First Dosing
Day -1 – Admission to CRU 
Day prior to Period 1 Dosing
Reference
Test
Release from CRU (24 Hours post Period 1 Dose)
Day -1 – Admission to CRU 
Day prior to Period 2 Dosing
Release from CRU (24 Hours post Period 2 Dose
FU
Test
Reference
7 days between teduglutide dose in Period 1 and Period 2
7 (± 2) days after the last study drug administration
FU=Follow up
Fixed teduglutide dose (delivered by pen injector [test] or from approved single-use vials [reference]) is 3 mg for 
subjects in Cohort 1 (≥40.0 kg to ≤75.0 kg) and 4mg for subjects in Cohort 2 (>75.0 kg to ≤120.0 kg)
Cohort 1 (3 mg Teduglutide) and Cohort 2 (4 mg Teduglutide)
2-Period Crossover
For non-commercial use only


Takeda
CONFIDENTIAL
Page 13
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
3.
SCHEDULE OF STUDY PROCEDURES 
Study Proceduresa
Screeningb
Study Days in Each Period (Period 1 and Period 2)c
Washout
(7 days)c
ETe
FUf
Hours →
C-Id
Predose
0
0.5
1
2
3
4
5
6
8
10
12
14
16
24
Administrative Procedures
Visit
X
Informed Consent
X
Inclusion/Exclusion Criteria
X
Xg
Demography and Medical/Medication 
History
X
Safety Evaluations 
Full Physical Examinationh
X
Xm
X
Abbreviated Physical Examinationh
X
Xn
Height
X
Weight
X
X
12-Lead ECGi
X
Vital Signs (heart rate, blood pressure, 
respiratory rate, and temperature)i
X
Xj
X
X
X
Hematology, Serum Chemistryk, 
Coagulation (as appropriate), and 
Urinalysis 
X
X
X
X
Serum Pregnancy Test (females only)
X
Xl
Xm
X
Serum FSH (postmenopausal females 
only)
X
Urine Drug and Alcohol Screen
X
X
HIV, HBsAg, and HCV Antibodies
X
AE Monitoring
X
Concomitant Medication Monitoring
X
For non-commercial use only


Takeda
CONFIDENTIAL
Page 14
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Study Proceduresa
Screeningb
Study Days in Each Period (Period 1 and Period 2)c
Washout
(7 days)c
ETe
FUf
Hours →
C-Id
Predose
0
0.5
1
2
3
4
5
6
8
10
12
14
16
24
Study Drug Administration / PK
Teduglutide Administrationo
X
Blood for Teduglutide PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Procedures
Randomization
Xg
Injection Site Reaction and Injection 
Site Injury Assessment 
X
Xp
X
X
X
X
X
X
X
X
Device Malfunction Assessment
Xq
Confinement in the CRUr
X
AE=Adverse events; C-I=Check-in; CRU=Clinical research unit; ECG=Electrocardiogram; ET=Early termination; FSH=Follicle-stimulating hormone; FU=Follow-up; 
HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; HIV=Human immunodeficiency virus; PK=Pharmacokinetics
a
For details on Procedures, refer to Section 9.
b
Within 28 days prior to first teduglutide administration.
c
There will be a washout period of 7 days between the teduglutide dose in Period 1 and Period 2.
d
Subjects will be admitted to the CRU on Day -1 of each period at the time indicated by the CRU. Subjects may be admitted earlier for Coronavirus Disease 2019 (COVID-19) 
testing not related to study protocol as per CRU requirements. If the CRU decides to confine the subjects throughout the study (ie, washout period[s]), some safety events at 
check-in (eg, clinical laboratory test, urine drug and alcohol screen, pregnancy test, and vital signs) may not be performed at the investigator’s discretion.
e
To be performed prior to ET from the study. 
f
All subjects who received at least one dose of study drug (including subjects who terminate the study early) will be contacted by the CRU 7 (±2) days after the last study drug 
administration to determine if any AE has occurred since the last study visit.
g
Will be performed in Period 1 only. Subjects will be assigned to a cohort based on their weight and will receive the study treatments according to the randomization scheme. In 
each cohort, subjects will be randomized to 1 of 2 sequences and administered a single dose of teduglutide on Day 1 of each period per the randomization sequences, either AB or 
BA (as defined in the study protocol). To ensure adequate distribution across 3 injection sites (ie, thigh, abdomen, and arm), randomization will also be stratified by injection site 
within each cohort.
h
Full physical examinations will be performed at screening and prior to discharge at Period 2. Abbreviated physical examinations will be performed at check-in for each period 
and prior to release at Period 1 (See Section 9.2.1). Symptom-driven physical examinations may be performed at other times, if deemed necessary by the investigator or designee.
i
ECGs and vital signs will be performed after 5 minutes rest in the supine position.
j
To be performed within 24 hours prior to dosing in each period.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 15
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Study Proceduresa
Screeningb
Study Days in Each Period (Period 1 and Period 2)c
Washout
(7 days)c
ETe
FUf
Hours →
C-Id
Predose
0
0.5
1
2
3
4
5
6
8
10
12
14
16
24
k
Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of ET or rechecks, subjects may not have fasted for 8 hours prior to the serum 
chemistry sample being taken.
l
To be drawn at the same time as the clinical laboratory blood draw, result to be available prior to dosing.
m
To be performed on discharge from Period 2. 
n
To be performed prior to release from Period 1.
o
Each subject will receive teduglutide on 2 occasions, (ie, on Day 1 of each period, either by syringe injection [vial and syringe) or pen injector in a crossover fashion).
p
The injection sites will be assessed for injection site reactions and injection site injuries immediately postdose (ie, ≤2 minutes). 
q
To be performed for the test product (pen injector) during preparation, immediately prior, and post teduglutide administration.
r
Subjects will be confined in each period for at least 24 hours and will be released from the clinic following completion of the 24-hour study procedures. At all times, a subject 
may be required to remain at the CRU for longer at the discretion of the investigator or designee.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 16
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
4.
INTRODUCTION
4.1
Background
Teduglutide (ALX-0600, [gly2]-hGLP-2) is a novel, recombinant analog of naturally occurring 
human glucagon like peptide-2 (GLP-2), formulated for the treatment of short bowel syndrome 
(SBS). Teduglutide accelerates intestinal adaptation after bowel resection and enhances selective 
barrier function in the small intestine (Jeppesen et al., 2005; Jeppesen, 2007; Mardini and 
de Villiers, 2008). Data from previous investigations have shown functional changes in crypts 
and villi in humans following administration of teduglutide. The European Commission granted 
a centralized marketing authorization valid throughout the European Union (EU) for teduglutide 
(REVESTIVE®). A New Drug Application for teduglutide (GATTEX®) was approved by the 
United States (US) Food and Drug Administration (FDA) and teduglutide was recently approved 
for the treatment of patients aged ≥1 year with SBS in the EU, the US, and Canada. Teduglutide 
is currently approved in >30 countries.
Efficacy 
In pivotal and supportive clinical studies, the evidence demonstrates that teduglutide at a daily 
dose of 0.05 mg/kg administered SC is effective in treating parenteral support (PS)-dependent 
adults with SBS by providing a clinically meaningful reduction in weekly PS volume. The 
results are reproducible and generalizable across a broad population of adult SBS subjects. 
Results of the long-term extension studies demonstrate the reproducibility as well as the 
durability of the beneficial effects of teduglutide 0.05 mg/kg/day, without evidence for the 
development of tolerance during up to 30 months of treatment. In another extension study of 
subjects treated for an additional 24 months after receiving 24 weeks of teduglutide in the core 
study, the response to long-term treatment with teduglutide 0.05 mg/kg/day was maintained in 
subjects initially treated with teduglutide in the core study, with further reductions in PS volume 
relative to baseline and fewer days per week of PS support. The responses to treatment with 
teduglutide were accompanied by an increase in mean plasma citrulline, indicating increased 
enterocyte mass.
Pharmacokinetics
The PK of teduglutide has been investigated following single SC administration at fixed doses of 
2.5 to 10 mg (Study 1621/13). Following SC administration, the plasma Cmax of teduglutide 
occurred at approximately 3 to 4 hours postdose with the exposure (Cmax and AUC) increasing 
approximately in a dose proportional manner. Following a one-time PK sampling conducted at 
the beginning of the initial 24-week teduglutide treatment period (0.05 mg/kg SC once daily) in 
Study TED-C14-004, a maximum mean plasma concentration of 49.7 ng/mL was achieved at 
2.64±1.02 hours (tmax) and the mean AUC0-t and AUC0-inf values were 201±51.6 and 
204±51.1 ng•hr/mL, respectively. Teduglutide was absorbed and rapidly eliminated from plasma 
with mean t½ of 1.21±0.65 hours. The mean plasma clearance was 14.5±4.09 L/hr and the mean 
body weight normalized plasma clearance was 0.0259±0.0672 L/hr/kg. Teduglutide total 
exposure after SC administration was shown to be similar, irrespective of the site of 
administration (abdomen, arm, or thigh) (Study CL0600-015). 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 17
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Safety
The safety of teduglutide has been examined in 9 studies in healthy subjects. Teduglutide was 
well-tolerated in these studies. The AEs experienced by the healthy subjects were consistent with 
those experienced in clinical studies of SBS and Crohn’s subjects. There were no 
treatment-related SAEs or deaths reported in these studies. There were no clinically significant 
changes or results noted from clinical laboratory evaluations, vital sign measurements, ECG 
readings, or physical examination findings. The most common adverse reactions across all 
studies were abdominal pain, injection site reactions, nausea, headaches, abdominal distension, 
and upper respiratory tract infection. 
For further information on teduglutide, refer to the current edition of the Investigator’s Brochure 
(IB).
4.2
Rationale for the Proposed Study
A new pen injector is being developed to simplify the dose preparation and administration of 
teduglutide. Extensive in vitro device verification work will be performed to evaluate the safety 
and performance of the device. Device performance will evaluate dose accuracy and consistency 
of dose delivery using the pen injector in accordance with The International Organization for 
Standardization: 11608-1 standards.
This clinical bioavailability study is intended to support the bridging between the commercially 
available vial drug primary container administered via a syringe injection (eg, syringe and 
approved vials) versus the pen injector.
The purpose of this study is to evaluate the bioavailability of teduglutide administered as a single 
SC fixed dose (depending upon subject weightband assignment) delivered by a syringe injection 
and the same fixed dose delivered by the pen injector in healthy subjects.
Throughout the clinical development program for SBS, teduglutide has been administered daily 
by SC injection via arm, thigh, or abdomen based on individual subject body weight.
Currently the approved preparation and injection material includes off-the-shelf syringes (for 
manual injection) and needles. Therefore, a clinical bioavailability study is necessary to evaluate 
the exposure of fixed doses of teduglutide when administered by the pen injector (test) relative to 
the currently approved configuration by syringe injection (reference). Conducting such a study in 
healthy population is justifiable to avoid confounding factors from patients with SBS. 
Data from this study will be evaluated based on EMA Guideline CPMP/EWP/QWP/1401/98 
Rev. 1/ Corr. (EMA 2010) and the FDA’s Guidance for Industry: Bioavailability and 
Bioequivalence Studies Submitted in NDAs or INDs — General Considerations (FDA 2019).
The washout period between doses is considered sufficient to prevent carryover effects of the 
preceding treatment.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 18
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
4.3
Benefit/Risk Profile
The risks associated with dosing teduglutide are anticipated to be similar to those previously 
documented in the IB and product label for teduglutide and are not anticipated to induce any 
potential risk to healthy subjects participating in this study (current IB edition, GATTEX®, 
Prescribing Information, 2018).
The doses provided in the study are based on the dosing recommendations of the product label 
ie, approximately 5 mg for a 100 kg person, as the recommended daily dose of teduglutide is 
0.05 mg/kg body weight administered by SC injection once daily (GATTEX®, Prescribing 
Information, 2018).
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, vital signs, clinical laboratory tests, AE questioning, injection site reaction and 
injection site injury assessments, and physical examinations) are adequate to protect the subject’s 
safety and should detect all TEAEs.
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the subjects enrolled in this study is the free medical tests received at 
screening and during the study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 19
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
5.
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Hypothesis testing is not relevant for a bioavailability study.
5.2
Study Objectives
5.2.1
Study Primary Objective
To evaluate the bioavailability of teduglutide following the administration of a single, SC fixed 
dose of 3 mg or 4 mg teduglutide (depending upon subjects assignment in one of two cohorts as 
defined by body weight) administered via manual injection or via pen injector in healthy 
subjects.
5.2.2
Study Secondary Objectives
To evaluate the bioavailability of teduglutide, by injection site (ie, thigh, abdomen, and arm), 
following the administration of a single, SC fixed dose of 3 mg or 4 mg teduglutide (depending 
upon subjects assignment in one of two cohorts as defined by body weight) administered via 
manual injection or via pen injector in healthy subjects.
To evaluate other PK parameters of teduglutide, as appropriate, following the administration of a 
single dose of teduglutide administered via manual injection or pen injector in healthy subjects.
To assess the safety and tolerability of SC injections of teduglutide in healthy subjects.
To assess the safety and performance of the pen injector for SC drug administration in healthy 
subjects.
5.3
Endpoints
5.3.1
Primary Endpoints
The primary endpoints of the study are the PK metrics* and will include: 

AUC0-tlast: Area under the concentration curve from time zero to the time of last measurable 
concentration 

Cmax: Maximum concentration

AUC0-∞: Area under the concentration curve extrapolated to infinite time
*Beginning on Day 1 of each period, PK parameters will be calculated from reliable teduglutide 
concentration-time profiles using non-compartmental methods where all calculations will be 
based on actual sampling times.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 20
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
5.3.2
Secondary Endpoints 
The secondary endpoints will be assessed through evaluation of the following parameters: 
PK metrics* by injection site (ie, thigh, abdomen, and arm) including:

AUC0-tlast: Area under the concentration curve from time zero to the time of last measurable 
concentration 

Cmax: Maximum concentration

AUC0-∞: Area under the concentration curve extrapolated to infinite time
*Beginning on Day 1 of each period, PK parameters will be calculated from reliable teduglutide 
concentration-time profiles using non-compartmental methods where all calculations will be 
based on actual sampling times.

Other secondary PK parameters will include:
tmax: Time of first occurrence of Cmax
z: Terminal disposition phase rate constant
t1/2: Terminal disposition phase half-life
CL/F: Apparent total body clearance for extravascular administration divided by the fraction 
of dose absorbed
Vz/F: Apparent volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose absorbed

Occurrence of TEAEs, including injection site reactions and injection site injury assessments.

Routine clinical safety monitoring that includes: vital signs, clinical laboratory test results 
(hematology, serum chemistry, coagulation (as appropriate), and urinalysis) and physical 
examinations.

Occurrence of device malfunctions.
The safety endpoint and safety variables will be captured for both test and reference.
A list of potential device malfunctions will be provided to the study site as a reference list for 
data capture.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 21
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
6.
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a randomized, open-label, two-treatment, two-period, two-sequence, single dose, 
crossover bioavailability study in healthy adult subjects.
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dosing. 
Subjects will be enrolled into 1 of 2 cohorts based on their weight (≥40.0 kg to ≤75.0 kg 
[Cohort 1] and >75.0 kg to ≤120.0 kg [Cohort 2]). In each cohort, subjects will be admitted to the 
clinical facility the day prior to each dosing and will be confined at least 24 hours; subjects will 
be released following completion of the 24-hour study procedures in each period. On Day 1 of 
Period 1, subjects in each cohort will be randomized to 1 of 2 treatment sequences as indicated in 
Table 2 below. Fixed teduglutide doses (delivered by pen injector or from approved single-use 
vials) is 3 mg for subjects in Cohort 1 and 4 mg for subjects in Cohort 2. Each dose will be 
separated by a washout period of 7 days. Blood samples for teduglutide PK will be collected 
predose and for 24 hours following each teduglutide dose. 
Table 2
Treatment Scheme for Each Cohort
Weightband
Cohort/
Dose level
No. of 
Subjects
Sequence*
Treatment 
Period 1
(Day 1)
Washout 
Period
(7 days)
Treatment 
Period 2
Day 1)
≥40.0 kg - ≤75.0 kg
Cohort 1 / 
3 mg
n=16
AB
Reference
(fixed dose by 
vial and 
syringe)**
→
Test
(fixed dose by 
pen injector)**
>75.0 kg - ≤120.0 kg
Cohort 2 / 
4 mg
n=16
≥40.0 kg - ≤75.0 kg
Cohort 1 / 
3 mg
n=16
BA
Test
(fixed dose by 
pen 
injector)**
→
Reference
(fixed dose by 
vial and 
syringe)**
>75.0 kg - ≤120.0 kg
Cohort 2 / 
4 mg
n=16
* To ensure adequate distribution across 3 injection sites (ie, thigh, abdomen, and arm), randomization will be 
stratified by injection site within each cohort.
**Fixed teduglutide doses (delivered by pen injector or from approved single-use vials) is 3 mg for subjects in Cohort 1 
(≥40.0 kg - ≤75.0 kg) and 4mg for subjects in Cohort 2 (>75.0 kg - ≤120.0 kg).
Treatment A: Teduglutide administered by syringe injection 
Treatment B: Teduglutide administered by pen injector
Safety and tolerability will be assessed by TEAEs, including injection site reaction and injection 
site injury assessments, clinical laboratory evaluations, physical examinations, and vital signs.
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will be contacted by the CRU 7 (±2) days after the last study drug administration to 
determine if any AE has occurred since the last study visit.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 22
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
6.2
Dose Escalation
Not applicable.
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
The purpose of the study is to test the bioavailability between the two administration devices. By 
using healthy subjects, the study will mainly focus on the difference in the exposure between the 
two devices and limit other factors on the dose-exposure response. In order to manage the 
variability in drug preparation and administration, the site staff will be fully trained in drug 
administration.
Subjects will be randomized to treatment sequences to minimize assignment bias. A weight 
stratified, crossover design is used to reduce the residual variability as every subject acts as their 
own control. To ensure adequate distribution across 3 injection sites (ie, thigh, abdomen, and 
arm), randomization will also be stratified by injection site within each cohort.
The washout period between doses is considered sufficient to prevent carryover effects of the 
preceding treatment.
6.3.2
Rationale for Dose 
Teduglutide is indicated for the treatment of adult and pediatric patients with SBS. The European
Commission granted a centralized marketing authorization valid throughout the EU for 
teduglutide (REVESTIVE®). A New Drug Application for teduglutide (GATTEX®) was 
approved by the US FDA and teduglutide was recently approved for the treatment of patients 
aged ≥1 year with SBS in the EU, the US, and Canada. Teduglutide is currently approved in 
>30 countries. Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in 
clinical studies in adults with SBS.
To simplify dosing procedures and reduce dosing errors, a dosing regimen based on weightbands 
was explored by population PK modeling and simulation (including PK and exposure-response 
analyses) based on the available clinical data. The 2 weightbands proposed are (based on 
modeling) ≥40.0 kg to ≤75.0 kg (Cohort 1) and >75.0 kg to ≤120.0 kg (Cohort 2). Any subject in 
the weightband of ≥40.0 kg to ≤75 kg (Cohort 1) will receive a fixed 3 mg single dose and the 
weightband of >75.0 kg to ≤120.0 kg (Cohort 2) will receive a fixed 4 mg single dose. The 
proposed fixed doses are expected to deliver comparable exposures to those when using the 
weight-based dose of 0.05 mg/kg once daily.
6.3.3
Rationale for Endpoints
6.3.3.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this bioavailability study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 23
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
6.3.3.2
Safety, Tolerability, and Performance Endpoints 
The key safety and tolerability endpoints are typical for Phase 1 studies. The sampling time 
points selected for AEs, vital signs, clinical laboratory assessments, and injection site reaction 
injection site injury assessments are considered sufficient to assess safety and detect any TEAEs.
As the study is investigating the potential of a new pen injector to deliver teduglutide, a list of 
potential device malfunctions will be provided to the study site as a reference list for data 
capture. The pen injector will be evaluated prior to and post teduglutide administration. The site 
staff will report any malfunctions whilst using the device.
6.3.4
Future Biomedical Research 
Not applicable.
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
teduglutide, and is to be collected as close to the scheduled times defined in this protocol as 
possible. 
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drug to any subject may not be modified. If necessary, 
a subject may be discontinued for the reasons described in Section 7.5. Discontinued subjects 
may be replaced at the discretion of the Sponsor and the investigator.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first subject.
6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure (ie, the follow-up 
contact on Day 7 [±2 days] for all subjects including those who received at least one dose of 
study drug and withdrawn early) as outlined in the Schedule of Study Procedures (Section 3).
6.5.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in the follow-up contact for 
the last subject in the study. 
This time period may change in the event that the study is terminated early or the last subject is 
lost to follow-up.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 24
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
6.5.4
Definition of Study Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is 
no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.5.6
Criteria for Premature Termination or Suspension of a Site
There is no predetermined criteria for termination of suspension of a site. 
Termination or suspension of a site may occur at any time at the discretion of the Sponsor.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 25
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
7.
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study:
1.
An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2.
Ability to voluntarily provide written, signed, and dated informed consent and assent as 
applicable to participate in the study.
3.
Aged 18 - 45 inclusive at the time of consent. The date of signature of the informed 
consent is defined as the beginning of the screening period. This inclusion criterion will 
only be assessed at the first screening visit.
4.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential, refer 
to Appendix D.
5.
Considered “healthy” by the investigator. Healthy status is defined by absence of evidence 
of any active or chronic disease following a detailed medical and surgical history, a full 
physical examination including vital signs, 12-lead ECG, hematology, coagulation (as 
appropriate), serum chemistry, and urinalysis.
6.
BMI ≥18.0 and ≤32.0 kg/m2 at screening. Body weight for a subject in Cohort 1 will be 
≥40.0 kg to ≤75.0 kg, and body weight for a subject in Cohort 2 will be >75.0 kg to 
≤120.0 kg, inclusive. This inclusion criterion will be assessed at the screening visit and 
confirmed at first check-in.
7.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
1.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect 
the action, absorption, or disposition of the investigational product, or clinical or laboratory 
assessments.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to fully complete the study, or any condition 
that presents undue risk from the investigational product or procedures.
3.
Positive PCR test for SARS-CoV-2, either with the absence or presence of the clinical 
symptoms of COVID-19.
4.
Known or suspected intolerance or hypersensitivity to teduglutide, closely-related 
compounds, or any of the stated ingredients.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 26
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
5.
Significant illness, as judged by the investigator, within 2 weeks of the first dose of 
teduglutide.
6.
Known history of alcohol or other substance abuse within the last year prior to screening.
7.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of teduglutide.
8.
Pregnant or lactating female.
9.
Within 30 days prior to the first dose of teduglutide:

Have used an investigational product (if elimination half-life is <6 days, otherwise 
5 half-lives).

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s (or designee’s) opinion, may impact this study.

Have had any substantial changes in eating habits, as assessed by the investigator 
(or designee).
10.
Use of dipeptidyl peptidase 4 inhibitors within 30 days or 5 half-lives, whichever is 
greater, prior to administration of the first dose of teduglutide.
11.
Confirmed systolic blood pressure >140 mmHg or <90 mmHg, and diastolic blood 
pressure >90 mmHg or <40 mmHg at screening.
12.
Twelve (12)-lead ECG demonstrating QTcF >450 msec at screening. If the QTcF exceeds 
the aforementioned limits, the ECG should be repeated 2 more times and the average of the 
3 QTcF values should be used to determine the subject’s eligibility.
13.
Positive screen for drugs of abuse or alcohol at screening and at each check-in.
14.
Male subjects who consume more than 21 units of alcohol per week or regularly consume 
more than 3 units per day. Female subjects who consume more than 14 units of alcohol per 
week or regularly consume more than 2 units per day. (1 alcohol unit=150 mL of wine, or 
360 mL of beer, or 45 mL of 45% alcohol).
15.
Positive HIV, HBsAg, or HCV antibody screen at screening.
16.
Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products 
in any form (eg, gum, patch) based on subject self-reporting. Ex-users must report that they 
have stopped using tobacco for at least 3 months prior to receiving the first dose of 
teduglutide.
17.
Routine consumption of more than 2 units of caffeine per day or subjects who experience 
caffeine withdrawal headaches. One caffeine unit is contained in the following items: 
one 6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz (360 mL) cup 
of tea, three 1 oz (85 g) chocolate bars.
18.
Prior screen failure, randomization, participation, or enrollment in this study, or prior 
exposure to any GLP-2 analogs.
19.
Presence of lesions, rashes, tattoos, and moles etc. on administration sites not allowing 
adequate conduct of injection site reaction and injection site injury assessments.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 27
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
20.
Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations; with the exception of occasional use of ibuprofen [1.2 g per 24 hour period] 
or acetaminophen [2 g per 24 hour period]). Current use is defined as use within 14 days of 
the first dose of teduglutide and throughout the study.
7.3
Excluded Medications, Supplements, Dietary Products 
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. 
After the first dose, ibuprofen (1.2 g per 24 hour period) or acetaminophen (up to 2 g per 24 hour 
period) may be administered at the discretion of the investigator or designee.
If deviations occur, the investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in 
Table 3.
Table 3
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Randomization 
(Days -28 to predose [Day 1 Period 1])
Post-Randomization (Day 1 
Period 1) up to Last PK Sample 
Collection
Alcohol
Prohibited from 48 hours prior to first dosing 
Prohibited from first dosing in 
Period 1 and Period 2 until the 
completion of the last PK sample in 
each period 
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing 
Prohibited from first dosing in 
Period 1 and Period 2 until the 
completion of the last PK sample in 
each period
Medications
See Section 7.1 and Section 7.2a
See Section 7.1 and Section 7.2a
Nicotine- and tobacco-
containing products
Prohibited from 3 months prior to first 
dosing 
Prohibited from first dosing in 
Period 1 until the completion of the 
last PK sample in Period 2
a
If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the Sponsor and investigator.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
When confined, standard meals and snacks will be provided at appropriate times, except when 
subjects are required to fast. The meals served on the day of dosing should be identical for each 
treatment arm in the study. 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 28
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
7.4.2
Activity
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the 
study.
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when 
they are supine or semi-reclined for study procedures. 
However, should AEs occur at any time, subjects may be placed in an appropriate position or 
will be permitted to lie down on their right side.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the investigator or designee for the 
following reasons:

A positive pregnancy test for females.

Positive urine drug or alcohol results.

Difficulties in blood collection.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the end-of-study or early termination as described in Section 3.
7.7
Subject Replacement
Replacement of discontinued or withdrawn subjects due to any reason will be assessed on a case 
by case basis to ensure a minimum of 14 subjects complete each treatment sequence (per cohort 
weightband) within each cohort of the study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 29
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
8.
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Teduglutide will be administered as a subcutaneous (SC) injection only. 
Subjects will receive teduglutide in each period either by a syringe injection ([syringe and vial], 
reference; Treatment A) or a pen injector (test; Treatment B) as single SC fixed doses, based on 
subject weightband assignment (≥40.0 kg to ≤75.0 kg [Cohort 1] and >75.0 kg to ≤120.0 kg 
[Cohort 2]). 
Cohort 1 will receive 3 mg teduglutide and Cohort 2 will receive 4 mg teduglutide.
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of teduglutide products, including supplies for 
retention, and pre-filled pen injectors to allow completion of this study. The same lot number 
will be used throughout the study. Full details pertaining to pharmacy and dosing supplies will be 
described in a separate document.
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report. Study drugs will be stored according to the product labels provided 
with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drug supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
8.1.4
Randomization Code Creation and Storage 
Subjects who complete the study screening assessments and meet all the eligibility criteria will 
be assigned a unique randomization identification number at the time of the first dosing, different 
from the screening number, and will receive the corresponding product, according to a 
randomization scheme generated at Celerion. 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 30
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Subjects will be assigned to a cohort based on their weight and then provided the study 
treatments according to the randomization scheme. In each cohort, subjects will be randomized 
to 1 of 2 sequences and administered a single dose of teduglutide on Day 1 of each period per 
randomization sequences, either AB or BA as outlined in Table 2. To ensure adequate 
distribution across 3 injection sites (ie, thigh, abdomen, and arm), randomization will also be 
stratified by injection site within each cohort.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused study drugs will be retained by Celerion, or 
destroyed, as per Sponsor instructions. Unused pen injectors will be returned to the Sponsor, or 
destroyed at Sponsor request. If no supplies remain, this fact will be documented in the 
pharmacy product accountability records. 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 31
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
9.
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date 
an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Allocation Numbers
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of dosing, different from the screening number.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
This is a 2-way, crossover study. All subjects will receive study drugs as detailed in Section 6.1.
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.3. All medications taken by 
subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the investigator or designee and/or the Sponsor 
for reasons related to subject safety.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 32
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
For this study, the collection of blood for teduglutide PK is the critical parameter and needs to be 
collected as close to the exact time point as possible. All other procedures should be completed 
as close to the prescribed/scheduled time as possible, but can be performed prior to or after the 
prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
The blood collection time deviation windows are presented below:
Protocol Hour
Deviation Window
Predose
≤ - 2 minutes (prior to dose)
>0.0 – 8.0 hour
≤ ± 2 minutes
>8.0 – 24.0 hour
≤ ± 5 minutes
9.2.1
Full Physical Examination
A full physical examination will be performed at screening and end of Period 2 as outlined in the 
Schedule of Study Procedures (Section 3). 
An abbreviated physical exam will be performed at check-in for each period and prior to release 
in Period 1. An abbreviated physical examination will include at the minimum, examination of 
respiratory, cardiovascular, and gastrointestinal systems, with the option for further examination 
of additional systems as necessary based on reported symptoms/AEs.
Symptom-driven physical examinations may be performed at other times, if deemed necessary 
by the investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study 
Procedures (Section 3).
9.2.3
Body Mass Index (BMI)
BMI will be calculated based on the height and weight measured at screening. If applicable, BMI 
will be recalculated with the subsequent measures of height from screening and the most current 
weight measurement.
9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, will 
be measured as outlined in the Schedule of Study Procedures (Section 3). Additional vital signs 
may be taken at any other times, if deemed necessary.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 33
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Vital signs measurements will be performed following 5 minutes rest in a supine position, except 
when they are seated or semi-reclined because of study procedures and/or AEs (eg, nausea, 
dizziness) or if deemed necessary by the investigator or designee.
At the predose time points, vital signs will be measured within 24 hours prior to dosing in each 
period. When scheduled postdose, vital signs will be performed within approximately 15 minutes 
of the scheduled time point.
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3). Additional ECGs may be taken at any other times, if deemed necessary by the 
investigator or designee.
ECGs will be performed following 5 minutes rest in the supine position. All ECG tracings will 
be reviewed by the investigator or designee.
At screening, if the QTcF exceeds the limits as referenced in Section 7.2, the ECG should be 
repeated 2 more times and the average of the 3 QTcF values should be used to determine the 
subject’s eligibility.
9.2.6
Injection Site Reaction and Injection Site Injury Assessments 
Local tolerability, reactions, and injuries at the injection site will be evaluated by the 
investigator/designee as indicated in Section 3. Local tolerability will be assessed before, during, 
and after the end of the infusion at the time points.
Additionally, Subjects will be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, injection site pain, redness, bruising, and/or swelling, etc, that may represent 
an administration-related reaction or injury to the study medication or administration method. 
Subjects will be asked to report AEs to the CRU staff immediately as they are experienced. 
Appropriate treatment and follow-up will be determined by the investigator. Subjects with a 
severe or serious administration-related reaction (eg, shortness of breath, wheezing, stridor, 
angioedema, life-threatening change in vital signs, severe injection site reactions) must be 
withdrawn from the study and treated and followed up appropriately. 
Any injection site reaction or injury will be collected and graded as mild, moderate, or severe.
Additional instructions concerning the collection of injection site reactions and injuries will be 
provided to the site prior to study start.
9.2.7
Study Drug Administration
Prior to receiving the first dose of teduglutide, subjects are to be randomized to a treatment as 
depicted in Table 1.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 34
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
In each period, subjects will receive teduglutide administered SC to the arm, thigh, or abdomen 
either by syringe injection (syringe and vial) or pen injector. The same location (ie, arm, thigh or 
abdomen) but different puncture spot will be used for administration in the subsequent period. 
Time of administration and administration site location will be recorded. 
Additional administration instructions will be provided in a separate document for the test 
injection 
Administration of teduglutide reference will be done according to the full prescribing 
information of teduglutide (GATTEX®, Prescribing Information, 2018).
9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drugs and/or 
procedures as described in Section 10.
9.2.9
Laboratory Procedures and Assessments
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry 
sample being taken.
Chemistry evaluations will consist of the following standard serum chemistry panel:
Blood Urea Nitrogen
Albumin
Bilirubin (total and direct)
Sodium
Alkaline phosphatase 
Potassium
Aspartate aminotransferase (AST)
Chloride
Alanine aminotransferase (ALT)
Glucose 
Lipase
Creatinine *
Amylase
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 35
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
Other 
PCR Test (COVID-19)
Urine drug screen

Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)

Amphetamines

Barbiturates

Benzodiazepines

Cocaine

Cannabinoids
HIV test
HBsAg
HCV (if antibody positive, confirm ribonucleic acid 
negative)
Urine alcohol screen
Female subjects only
Serum human chorionic gonadotropin (hCG) (for 
pregnancy)
FSH (to confirm postmenopausal status, as applicable) 
Coagulation*
Coagulation evaluations will consist of the following tests:
Prothrombin time
International normalized ratio (INR)
* To be performed for subjects who develop ALT >3x upper limit of normal (ULN) (See Section 10.2.7.5).
9.3
PK Samples
Instructions for PK sample collection, processing, and shipping will be provided in separate 
documents.
Primary specimen collection parameters are provided in Table 4.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 36
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Table 4
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample
Plasma
Plasma sample for PK 
analysis
Mandatory
9.3.1
PK Measurements 
The following PK parameters will be calculated from plasma concentrations of teduglutide, 
unless otherwise specified:
Pharmacokinetic Parameter
Definition
AUC0-tlast
Area under the concentration curve from time zero to the last measurable 
concentration
AUC0-∞
Area under the concentration curve extrapolated to infinite time
Cmax
Maximum concentration 
tmax
Time of first occurrence of Cmax
z
Terminal disposition phase rate constant
t½
Terminal disposition phase half-life
CL/F
Apparent total body clearance for extravascular administration divided by 
the fraction of dose absorbed
Vz/F
Apparent volume of distribution associated with the terminal slope 
following extravascular administration divided by the fraction of dose 
absorbed
No value for AUC0-∞, z or t½ will be reported for cases that do not exhibit a terminal log linear 
phase in the concentration time profile.
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations.
PK parameters will be calculated from reliable teduglutide concentration-time profiles using 
non-compartmental methods where all calculations will be based on actual sampling times.
Individual and mean serum concentration time curves (both linear and log linear) will be 
included in the final report.
9.3.2
Biomarker Measurements 
Not applicable.
9.3.3
PGx Measurements 
Not applicable.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 37
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
9.3.4
Confinement
Subjects will be housed the day before dosing in each period until the last PK sample is collected 
and the 24-hour study procedures are completed for each period, at which time subjects will be 
released from the clinic. Check-in times for each period will be indicated by the CRU. Subjects 
may be admitted earlier for COVID-19 testing not related to study protocol as per CRU 
requirements.
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will be contacted by the CRU 7 (±2) days after the last study drug administration to 
determine if any AE has occurred since the last study visit. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
investigator or designee.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 38
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
10.
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
whether or not it is considered related to the drug.
An AE also means any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other 
persons, in the context of a clinical investigation, whether or not related to the investigational 
device.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. 
In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 39
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or 
complication of such a concurrent medical history condition, the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis),
worsening of the condition should only be captured as an AE if occurring to a greater extent 
to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration 
of study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a 
change in study medication or investigational device, the event should be captured once with 
the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as an AE. Complications resulting from 
any planned surgery should be reported as AEs.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 40
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to 
decide whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the case report form (CRF), in order to capture this important safety information 
consistently in the database. AEs associated with an overdose will be documented on AE 
CRF(s) according to Section 10.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.7.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” 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 that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 5).
For non-commercial use only


Takeda
CONFIDENTIAL
Page 41
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Table 5
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular tachycardia
Acute liver failure
Malignant hypertension
Anaphylactic shock
Convulsive seizures
Acute renal failure
Agranulocytosis
Pulmonary hypertension
Aplastic anemia
Pulmonary fibrosis
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected endotoxin shock
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19 pneumonia
Confirmed or suspected transmission of infectious agent by a 
medicinal product
COVID-19-related disease
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be 
considered as “Important Medical Events” satisfying SAE reporting requirements.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.1 and Section 10.1.1).
10.1.2
Special Interest AEs
One subject had a cecal polyp identified during a colonoscopy (SHP633-304). This event was 
reported as an AE of special interest of large intestinal polyp that was assessed as moderate in 
intensity and related to teduglutide by the investigator.
Based on the pharmacologic activity and findings in animals, teduglutide has the potential to 
cause hyperplastic changes, including neoplasia, in the small bowel and hepatobiliary tract. 
Further details are provided in the current IB edition. 
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event 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:
An adverse event that is usually alleviated with additional 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 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 42
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be ruled 
out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not 
Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or
investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Drug interrupted – the dose was interrupted due to the particular AE.

Outcome 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 43
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; 
the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.7
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
Liver Function Tests
10.2.7.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal Liver Function Tests) 
will commence at the time the subject signs the informed consent. Routine collection of AEs will 
continue until the follow-up phone call on Day 8 (±2 days) of Period 2, approximately 7 days 
after the last dose of investigational product. For subjects who discontinue prior to the 
administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
10.2.7.2
Reporting AEs
At each study visit and at the follow-up contact, the investigator or designee will assess whether 
any subjective AEs have occurred. A neutral question, such as “How have you been feeling since 
your last visit?” may be asked. Subjects may report AEs occurring at any other time during the 
study. Subjects experiencing an SAE prior to the first exposure to investigational product must 
be monitored until the symptoms subside and any clinically relevant changes in laboratory values 
have returned to Baseline or there is a satisfactory explanation for the change. Nonserious AEs 
that begin prior to the first exposure to investigational product, related or unrelated to the study 
procedure, need not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 44
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
All AEs will be documented in the AE page of the CRF, whether or not the investigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.7.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 45
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.2.7.4
Reporting Special Interest AEs 
Occurrence of AEs of special interest as outlined in Section 10.1.2 will be reported directly to the 
Sponsor.
10.2.7.5
Close Monitoring and Treatment Discontinuation for Potential 
Drug-Induced Liver Injury (DILI)
Subjects who develop ALT >3x ULN after first dosing administration should be monitored 
closely and the clinical significance of the elevation should be assessed by the investigator. Close 
observation includes the following:

Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study drug has 
been discontinued and the subject is asymptomatic. 

Obtaining a more detailed history of symptoms and prior or concurrent diseases. 

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets. 

Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
Nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 

Obtaining a history of exposure to environmental chemical agents. 

Obtaining additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio [INR], direct bilirubin). 

Considering gastroenterology or hepatology consultations. 
If a subject develops any of the following after the first dose, treatment should be discontinued, 
the medical monitor should be contacted immediately, and the subject should be withdrawn from 
the study: 

ALT or AST >8xULN

ALT or AST >5xULN at the end of the 7 day washout period
For non-commercial use only


Takeda
CONFIDENTIAL
Page 46
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020

ALT or AST >3xULN and (total bilirubin >2xULN or INR >1.5)

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
All subjects showing possible DILI should be followed until all abnormalities return to normal or 
to the baseline state. Pertinent elements of the case should be captured in the DILI CRF. 
10.2.8
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national regulations. 
The Sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the study. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 47
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
11.
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP will be prepared and finalized 
before database lock. A separate PK analysis plan will be finalized prior to database lock. These 
documents will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate.
11.1.1
Analysis Sets
11.1.1.1
PK Set
All subjects who comply sufficiently with the protocol and display an evaluable PK profile for 
both periods (exposure to treatment, availability of measurements, completion of washout period, 
and absence of major protocol violations) will be included in the statistical analyses.
11.1.1.2
Safety Set
All subjects who received at least one dose of the study drug will be included in the safety 
evaluations.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3
PK Analysis
Statistical analysis of PK data will be based on the PK analysis data set. 
All individual concentration data and PK metrics will be listed for each subject and treatment 
together with summary statistics such as geometric mean, median, arithmetic mean, SD, 
coefficient of variation, geometric coefficient of variation, and minimum and maximum grouped 
by treatment and cohort. The time until first occurrence of Cmax is reached (tmax) will be also 
listed for each subject and treatment and summarized by medians, minimum and maximum 
grouped by treatment and cohort. The number of time points of the terminal log-linear phase 
used to estimate the terminal rate constant (z) and the residual area will be also provided for 
each subject and treatment. 
Individual concentration-time curves will be presented in linear/linear and log/linear scale. 
Figures showing the mean (with ±SD as error bars) as well as the median (with 25th to 75th
quantiles as error bars) concentration time profiles grouped by treatment and cohort will be also 
presented in linear/linear and log/linear scale. The PK endpoints will also be analyzed by 
injection site (ie, thigh, abdomen, and arm).
For non-commercial use only


Takeda
CONFIDENTIAL
Page 48
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
PK metrics AUC0-tlast, AUC0-∞, and Cmax, will be analyzed using an ANOVA model for each 
cohort separately. 
PK metrics will be transformed prior to analysis using a logarithmic transformation. The 
difference in means and the corresponding two-sided 90% CI on the log-transformed scale will 
be obtained from that model. The difference in means and the corresponding CI will be 
back-transformed to obtain the ratio of geometric means and the corresponding two-sided 
90% CI for the ratio on the original scale. The terms used in the ANOVA model will be 
sequence, subject within sequence, period and treatment. According to EMA guideline 
(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr) (EMA 2010), subjects who will not provide evaluable 
data for both periods will not be included and fixed effects will be used for all terms.
To assess bioavailability between test and reference, the 90% CI for the ratio of geometric means 
for PK metrics, AUC0-tlast, AUC0-∞, and Cmax will be derived and compared (and would be 
contained within the acceptance interval of 80.00 to 125.00% if bioequivalent).
11.1.4
Pharmacodynamic Analysis 
Not applicable.
11.1.5
Safety Analysis
Statistical analysis of safety data will be based on the safety analysis data set.
Safety data will be listed by subject and summarized by cohort and treatment using descriptive 
statistics. Continuous variables will be summarized by sample size, mean, SD, median, 
minimum, and maximum. Categorical variables will be summarized by number of subjects and 
the percent of subjects in each category.
TEAEs will be analyzed using the number and percentage of subjects reporting events, as well as 
the number of events, by system organ class and preferred term, severity, and causal relationship 
to the study treatment and device. Among TEAEs, injection site reactions and injection site 
injuries will be analyzed using the number and percentage of subjects reporting events, by 
preferred term, severity, and causal relationship to study treatment and device. Laboratory tests, 
vital signs, physical examinations, and corresponding changes from baseline will be summarized 
by study visit where baseline will be defined as the last non-missing assessment on or before 
Day 1 prior to the first dose.
Device malfunctions will be listed for each subject and summarized by cohort using the number 
and percentage of events.
11.2
Interim Analysis and Criteria for Early Termination
Not applicable.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 49
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
11.3
Determination of Sample Size
The overall power for the endpoints (AUC0-tlast, AUC0-∞, and Cmax) with a total sample size of 
64 subjects will be 92.6% power based on a 5% type 1 error and a Coefficient of Variation of 
21%, assuming a true ratio of test/reference of 1.0 in their relative bio-availabilities based on the 
acceptance interval of 80.00 to 125.00%. The sample size of 28 subjects within each cohort 
(14 each sequence) was accounted for approximately 10% potential drop-outs and/or 
non-reliable concentration time-profiles to yield 32 subjects per cohort (16 subjects per sequence 
within each cohort). This sample size was calculated with SAS v9.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 50
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
12.
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site may be made periodically during the study to ensure that all 
aspects of the protocol are followed. Due to COVID-19, monitoring visits may also be conducted 
remotely. Source documents will be reviewed for verification of data recorded on the CRFs. 
Source documents are defined as original documents, data, and records. The investigator and 
study site guarantee access to source documents by the Sponsor or its designee (contract research 
organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
Sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
For COVID-19-related protocol deviations, the specific protocol deviation, the reason for the 
deviation, and the relationship to COVID-19 should be documented using CRU standard 
processes.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the Sponsor should 
be notified immediately. The investigator guarantees access for quality assurance auditors to all 
study documents as described in Section 12.1.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 51
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
13.
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council on Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The Sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the informed consent 
form, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor 
has confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor 
has received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 52
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study, and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the Sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 53
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 54
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting study 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide 
the Sponsor with a written notice requesting that their information not be listed on the registry 
site.
13.4.3
Clinical Study Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the Sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 55
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
14.
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information - SAE
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Shire
Fax: 
E-mail: 
14.1.2
Study Contact Information – Product Quality Complaint 
Contact Type / Role
Contact
Product Quality Complaint
Shire
Tel:
E-mail: 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 56
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
14.1.3
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the Sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also to protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation, E6(R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.8 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
For non-commercial use only


Takeda
CONFIDENTIAL
Page 57
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
14.1.4
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.5
List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC0-∞
Area under the concentration curve extrapolated to infinite time
AUC0-tlast
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method.
BMI
Body mass index
CFR
Code of Federal Regulations
CI
Confidence interval
cm
Centimeter
Cmax
Maximum observed concentration 
COVID-19
Coronavirus Disease 2019
CRF
Case report form
CRU
Clinical Research Unit
DNA
Deoxyribonucleic acid 
DILI
drug-induced liver injury 
ECG
Electrocardiogram
EU
European Union
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GLP-2
Glucagon-like peptide 2
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ID
Identifier
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
kg
Kilogram
m2
Meters squared
For non-commercial use only


Takeda
CONFIDENTIAL
Page 58
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
oz
Ounce 
PCR
Polymerase chain reaction
PK
Pharmacokinetic(s)
PS
Parenteral support
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2 
SBS
Short-bowel syndrome
SC
Subcutaneous
SD
Standard deviation
SUSAR
Suspected unexpected serious adverse reaction
t½
Terminal disposition phase half-life
tmax
Time of first occurrence of Cmax
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
USA
United States of America
λz
Terminal disposition phase rate constant
For non-commercial use only


Takeda
CONFIDENTIAL
Page 59
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
15.
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). Drugs will be coded using the World Health 
Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed CRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor 
will make arrangements to train appropriate site staff in the use of the CRF. These forms are 
used to transmit the information collected in the performance of this study to the Sponsor and 
regulatory authorities. CRFs must be completed in English. Data are transcribed directly onto
CRFs.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The investigator must review the CRFs for completeness and accuracy and must sign and date 
the appropriate CRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the investigator with use of change and modification 
records of the CRFs. The Investigator must review the data change for completeness and 
accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the Sponsor.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 60
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms),
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8.0) until at least 2 years after the last approval of a marketing application for a 
specified drug indication being investigated or, if an application is not approved, until at least 
2 years after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6 Section 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the Clinical Study Site 
Agreement between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 61
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
16.
REFERENCES
Jeppesen, P. B. 2007. Growth factors in short-bowel syndrome patients. Gastroenterol Clin 
North Am, 36, 109-21, vii.
Jeppesen, P. B., Sanguinetti, E. L., Buchman, A., Howard, L., Scolapio, J. S., Ziegler, T. R., 
Gregory, J., Tappenden, K. A., Holst, J. & Mortensen, P. B. 2005. Teduglutide (ALX-
0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves 
intestinal function in short bowel syndrome patients. Gut, 54, 1224-31.
Mardini, H. E. & de Villiers, W. J. 2008. Teduglutide in intestinal adaptation and repair: light at 
the end of the tunnel. Expert Opin Investig Drugs, 17, 945-51.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 62
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued 
or that the regulatory authority has approved the marketing application. 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 63
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
The investigator should contact and receive written approval from the Sponsor before 
disposing of any such documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 64
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written informed consent 
form, the subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject or the 
subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 65
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or 
provided as a separate document) describing to the subject the contemplated and permissible 
uses and disclosures of the subject’s personal information (including personal health 
information) for purposes of conducting the study. The subject authorization must contain the 
following statements regarding the uses and disclosures of the subject’s personal 
information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active with a nonsterilized male partner must use highly effective 
contraception (as defined in the informed consent) from signing the informed consent and 
throughout the duration of the study, and for at least 30 days after the last dose of study drug. 
Regular pregnancy tests will be performed throughout the study for all female subjects.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 66
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
26. Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use highly effective contraception (as defined in the informed consent) from 
signing the informed consent throughout the duration of the study and for at least 90 days 
after the last dose of study drug. 
27. A statement that clinical trial information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 67
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 68
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects
From signing of informed consent, throughout the duration of the study, and for at least 90 days 
after last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for at least 30 days 
after last dose of study drug, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use a highly effective/effective method of contraception 
(from the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
* A woman is considered a woman of childbearing potential, ie fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH>40 IU/L) may be used to confirm a post-menopausal state in 
younger women (eg, those <45 year old) or women who are not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly). The only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal ligation.
–
Vasectomised partner (provided that partner is the sole sexual partner of the study 
subjects and that the vasectomised partner has received medical assessment of the 
surgical success).
For non-commercial use only


Takeda
CONFIDENTIAL
Page 69
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose until 30 days 
after last dose.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Hormonal contraception
3. Subjects will be provided with information on highly effective/effective methods of
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular hCG pregnancy tests will be performed for all women 
and all subjects (male and female) will receive continued guidance with respect to the 
avoidance of pregnancy and sperm or ova donation as part of the study procedures. Such 
guidance should include a reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (i.e., condom) in males with pregnant partners
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses; with the exception of female subjects using a protocol acceptable 
contraception method that has a known side effect of delayed or irregular menses), and, a 
negative serum hCG pregnancy test at each check-in prior to receiving any dose of study 
medication.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 70
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (i.e., condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
Sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 90 days after the last dose, should also be 
recorded following authorization from the subject’s partner. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the female subject was participating in a clinical study at 
the time she became pregnant and provide details of the study drug the subject received.
All pregnancies, including female partners of male subjects will be followed up to final outcome, 
using the pregnancy form. Pregnancies will remain blinded to the study team. The outcome, 
including any premature termination, must be reported to the Sponsor. An evaluation after the 
birth of the child will also be conducted.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 71
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Appendix E
Detailed Description of Amendments to Text
Amendment 1
Change 1. The term bioequivalence has been updated to bioavailability throughout the 
protocol. 
The change occurs in the protocol title and throughout the study protocol.
Initial 
wording 
(Title): 
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, 
Crossover Study to Evaluate the Bioequivalence of Teduglutide Administered 
Subcutaneously by Syringe Injection Versus Pen Injector in Healthy Adult 
Subjects
Amended 
or new 
wording 
(Title):
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, 
Crossover Study to Evaluate the Bioavailability of Teduglutide Administered 
Subcutaneously by Syringe Injection Versus Pen Injector in Healthy Adult 
Subjects
Change 2. The analysis conclusion for the primary objective has been modified. 
Due to the change from bioequivalence to bioavailability, the wording in the Synopsis -
Statistical Methodology for Pharmacokinetic Endpoints and in Section 11.1.3 (PK Analysis) 
has been modified.
Initial 
wording: 
To claim bioequivalence between test and reference, the 90% CI for the ratio of 
geometric means for PK metrics, AUC0-tlast, AUC0-∞, and Cmax, would be 
contained within the acceptance interval of 80.00 to 125.00%.
Amended 
or new 
wording:
To assess bioavailability between test and reference, the 90% CI for the ratio of 
geometric means for PK metrics, AUC0-tlast, AUC0-∞, and Cmax will be derived 
and compared (and would be contained within the acceptance interval of 80.00 
to 125.00% if bioequivalent).
Change 3. Hypothesis verbiage was removed from the study protocol. 
Hypothesis verbiage has been removed from Section 5.1 (Hypothesis).
Initial 
wording: 
The plasma PK (AUC0-tlast, AUC0-∞, and Cmax) of teduglutide following single 
SC administration by syringe injection (reference) and pen injector (test) will be 
bioequivalent, ie, the 90% CI for the ratio of geometric means for PK metrics, 
AUC0-tlast, AUC0-∞, and Cmax, are contained within the acceptance interval of 
80.00 to 125.00%.
Amended 
wording:
Hypothesis testing is not relevant for a bioavailability study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 72
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Change 4. Additional PK parameters have been added to the secondary endpoints. 
Additional PK parameters for CL/F (apparent total body clearance) and Vz/F (apparent volume 
of distribution) have been added to the following sections of the protocol: Synopsis (Criteria 
for Evaluation and Analyses), Section 5.3.2 (Secondary Endpoints), and Section 9.3.1 (PK 
Measurements)
New 
wording:
CL/F: Apparent total body clearance for extravascular administration 
divided by the fraction of dose absorbed
Vz/F: Apparent volume of distribution associated with the terminal slope 
following extravascular administration divided by the fraction of dose 
absorbed
Change 5. Sample size for the study has been updated.
The sample size for each cohort has been increased from 15 subjects to 16 subjects and the 
number of planned subjects has thus been updated from 60 to 64 subjects. The following 
sections were updated (Synopsis [Table 1, Planned Number of Subjects, and Sample Size 
Justification], Section 6.1 (Study Design [Table 2]), and Section 11.3 (Determination of 
Sample Size).
Initial 
wording: 
Weightband
Cohort/
Dose 
level
No. of 
Subjects
Sequence
Treatment 
Period 1
(Day 1)
Washout 
Period
(7 days)
Treatment 
Period 2
Day 1)
≥40.0 kg -
≤75.0 kg
Cohort 
1 / 3mg
n=15
AB
Reference
(fixed dose 
by vial and 
syringe)*
→
Test
(fixed dose 
by pen 
injector)*
>75.0 kg -
≤120.0 kg
Cohort 
2 / 4mg
n=15
≥40.0 kg -
≤75.0 kg
Cohort 
1 / 3mg
n=15
BA
Test
(fixed dose 
by pen 
injector)*
→
Reference
(fixed dose 
by vial and 
syringe)*
>75.0 kg -
≤120.0 kg
Cohort 
2 / 4mg
n=15
Amended 
wording:
Weightband
Cohort/
Dose 
level
No. of 
Subjects
Sequence
Treatment 
Period 1
(Day 1)
Washout 
Period
(7 days)
Treatment 
Period 2
Day 1)
≥40.0 kg -
≤75.0 kg
Cohort 
1 / 3mg
n=16
AB
Reference
(fixed dose 
by vial and 
syringe)*
→
Test
(fixed dose 
by pen 
injector)*
>75.0 kg -
≤120.0 kg
Cohort 
2 / 4mg
n=16
≥40.0 kg -
≤75.0 kg
Cohort 
1 / 3mg
n=16
BA
Test
(fixed dose 
by pen 
injector)*
→
Reference
(fixed dose 
by vial and 
syringe)*
>75.0 kg -
≤120.0 kg
Cohort 
2 / 4mg
n=16
For non-commercial use only


Takeda
CONFIDENTIAL
Page 73
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Initial 
wording: 
The planned total sample size for this study is 60 randomized subjects
Amended 
wording:
The planned total sample size for this study is 64 randomized subjects
Initial 
wording: 
The sample size of 26 subjects within each cohort (13 each sequence) would 
yield 86% power for the co-primary endpoints (AUC0-tlast, AUC0-∞, and Cmax) 
with a 5% type 1 error assuming a true ratio of test/reference of 1.0 in their 
relative bio-availabilities based on the acceptance interval of 80.00 to 125.00% 
and a Coefficient of Variation of 21%.
To account for approximately 10% potential drop outs and/or non-reliable 
concentration time-profiles, 30 subjects per cohort (15 subjects per sequence 
within each cohort) will be enrolled leading to a total sample size of 60 subjects. 
This sample size was calculated with Nquery.   
Amended 
wording:
The overall power for the endpoints (AUC0-tlast, AUC0-∞, and Cmax) with a total 
sample size of 64 subjects will be 92.6% power based on a 5% type 1 error and 
a Coefficient of Variation of 21%, assuming a true ratio of test/reference of 1.0 
in their relative bio-availabilities based on the acceptance interval of 80.00 to 
125.00%. The sample size of 28 subjects within each cohort (14 each sequence) 
was accounted for approximately 10% potential drop-outs and/or non-reliable 
concentration time-profiles to yield 32 subjects per cohort (16 subjects per 
sequence within each cohort). This sample size was calculated with SAS v9.
Change 6. The minimum number of subjects to complete each cohort has been increased. 
Verbiage in Section 7.7 (Subject Replacement) has been updated to reflect 14 subjects are to 
complete each cohort.
Initial 
wording: 
Replacement of discontinued or withdrawn subjects due to any reason will be 
assessed on a case by case basis to ensure a minimum of 13 subjects (per cohort 
weightband) complete each treatment in the study.
Amended 
wording:
Replacement of discontinued or withdrawn subjects due to any reason will be 
assessed on a case by case basis to ensure a minimum of 14 subjects (per cohort 
weightband) complete each treatment in the study.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 74
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Amendment 2
Change 1. The IB edition number has been removed from the protocol. Due to ongoing 
updates to the IB, the protocol will reference “the current edition” of the IB or “current IB 
edition” 
The change occurs in the following sections:
Section 4.1 - Introduction
Section 4.3 - Benefit/Risk profile
Section 10.1.2 - Special Interest AEs  
Initial 
wording: 
Investigator’s Brochure (IB Edition 16.0)
Amended 
or new 
wording:
The current edition of the Investigator’s Brochure (IB) (Section 4.2) or current 
IB edition (Section 4.3 and Section 10.1.2)
Change 2. Verbiage has been added to the pharmacokinetics section of the introduction to 
clarify study information source. 
The change occurs in the following section:
Section 4.1 - Introduction 
Initial 
wording: 
A maximum mean plasma concentration of 49.7 ng/mL was achieved at 
2.64±1.02 hours (tmax) and the mean AUC0-t and AUC0-inf values were 201±51.6 
and 204±51.1 ng•hr/mL, respectively. Teduglutide was absorbed and rapidly 
eliminated from plasma with mean t½ of 1.21±0.65 hours. The mean plasma 
clearance was 14.5±4.09 L/hr and the mean body weight normalized plasma 
clearance was 0.0259±0.0672 L/hr/kg.
Amended 
or new 
wording:
Following a one-time PK sampling conducted at the beginning of the initial 
24-week teduglutide treatment period (0.05 mg/kg SC once daily) in 
Study TED-C14-004, a maximum mean plasma concentration of 49.7 ng/mL 
was achieved at 2.64±1.02 hours (tmax) and the mean AUC0-t and AUC0-inf values 
were 201±51.6 and 204±51.1 ng•hr/mL, respectively. Teduglutide was absorbed 
and rapidly eliminated from plasma with mean t½ of 1.21±0.65 hours. The mean 
plasma clearance was 14.5±4.09 L/hr and the mean body weight normalized 
plasma clearance was 0.0259±0.0672 L/hr/kg.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 75
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Change 3. An exclusion criterion has been added for subject(s) with a positive COVID-19 test.
Additionally, the exclusion criterion in relation to the safety 12-lead ECG requirement and the 
inclusion criterion in relation to the age range (updated for Arizona state) has been updated.
The change occurs in the following sections:
Section 1 - Study Summary
Section 7.2 - Exclusion Criteria
Section 7.1 – Inclusion Criteria
Section 7.2 – Exclusion Criteria (Criterion 3 [new])
Initial 
wording: 
Not applicable
Amended 
or new 
wording:
Positive PCR (polymerase chain reaction) testing for severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2), either with the absence or presence of 
the clinical symptoms of COVID-19.
Section 7.2 - Exclusion Criteria (Criterion 12)
Initial 
wording: 
Twelve-lead (12)-ECG demonstrating QTcF >470 msec for females and 
>460 msec for males at screening. If the QTcF exceeds the aforementioned 
limits, the ECG should be repeated 2 more times and the average of the 3 QTcF 
values should be used to determine the subject’s eligibility.
Amended 
or new 
wording:
Twelve (12)-lead ECG demonstrating QTcF >450 msec at screening. If the 
QTcF exceeds the aforementioned limits, the ECG should be repeated 2 more 
times and the average of the 3 QTcF values should be used to determine the 
subject’s eligibility.
Section 7.1 – Inclusion Criteria (Criterion 3)
Initial 
wording: 
Aged 19 - 45 inclusive at the time of consent. The date of signature of the 
informed consent is defined as the beginning of the screening period. This 
inclusion criterion will only be assessed at the first screening visit.
Amended 
or new 
wording:
Aged 18 - 45 inclusive at the time of consent. The date of signature of the 
informed consent is defined as the beginning of the screening period. This 
inclusion criterion will only be assessed at the first screening visit.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 76
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Change 4. Verbiage has been included for the possible extension of confinement due to 
COVID-19 testing.
The change occurs in the following sections:
Section 3 - Schedule of Study Procedures 
Section 9.3.5 - Confinement
Initial 
wording: 
Subjects will be admitted to the CRU on Day -1 of each period at the time 
indicated by the CRU (Section 3).
Amended 
or new 
wording:
Subjects will be admitted to the CRU on Day -1 of each period at the time 
indicated by the CRU. Subjects may be admitted earlier for Coronavirus 
Disease-19 (COVID-19) testing not related to study protocol as per CRU 
requirements. If the CRU decides to confine the subjects throughout the study 
(ie, washout period[s]), some safety events at check-in (e.g., clinical laboratory 
test, urine drug and alcohol screen, pregnancy test, and vital signs) may not be 
performed at the investigator’s discretion.
Amended 
or new 
wording:
Subjects may be admitted earlier for COVID-19 testing not related to study 
protocol as per CRU requirements. (Section 9.3.5)
Change 5. Two additional conditions related to COVID-19 have been added to the Takeda 
Medically Significant AE list.
The change occurs in the following section:
Section 10.1.1 – SAEs (Table 5) 
Initial 
wording: 
Not Applicable.
Amended 
or new 
wording:
The terms COVID-19 pneumonia and COVID-19 related disease have been 
added to Table 5. In addition the following footnote to Table 5 has been added:
“Note: Terms identified on the Medically Significant AE List represent the 
broad medical concepts to be considered as “Important Medical Events” 
satisfying SAE reporting requirements.”
Change 6. Verbiage has been updated to allow for the possibility of remote monitoring due to 
COVID-19.
The change occurs in the following section:
Section 12.1 – Study Site Monitoring Visits 
For non-commercial use only


Takeda
CONFIDENTIAL
Page 77
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Initial 
wording: 
Monitoring visits to the study site will be made periodically during the study to 
ensure that all aspects of the protocol are followed.
Amended 
or new 
wording:
Monitoring visits to the study site may be made periodically during the study to 
ensure that all aspects of the protocol are followed. Due to COVID-19, 
monitoring visits may also be conducted remotely.
Change 7. Verbiage has been added relevant to the recording of protocol deviations 
surrounding COVID-19.
The change occurs in the following section:
Section 12.2 – Protocol Deviations 
Initial 
wording: 
Not Applicable.
Amended 
or new 
wording:
For COVID-19-related protocol deviations, the specific protocol deviation, the 
reason for the deviation, and the relationship to COVID-19 should be 
documented using CRU standard processes.
Change 8. As requested by the Food and Drug Administration, 2 additional injection sites were 
added. Subjects will also be randomized for injection site.
The change occurs in the following sections:
Section 1 - Synopsis (Table 1 and exclusion criteria)
Section 3 - Schedule of Study Procedures 
Section 6.1 - Study design (Table 2)
Section 6.3.1 - Rationale for Study Design
Section 7.2 - Exclusion Criteria
Section 8.1.4 - Randomization Code and Storage
Section 9.2.7 - Study Drug Administration
Initial 
wording: 
Not Applicable.
Amended 
or new 
wording:
The following verbiage has been added to Section 1, Section 6.3.1, and 
Section 8.1.4: “To ensure adequate distribution across 3 injection sites (ie, thigh, 
abdomen, and arm), randomization will be stratified by injection site within each 
cohort” 
Initial 
wording:
Will be performed in Period 1 only (Footnote “g” of Section 3 [Randomization])
For non-commercial use only


Takeda
CONFIDENTIAL
Page 78
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Amended 
or new 
wording:
Will be performed in Period 1 only. Subjects will be assigned to a cohort based 
on their weight and will receive the study treatments according to the 
randomization scheme. In each cohort, subjects will be randomized to 1 of 2 
sequences and administered a single dose of teduglutide on Day 1 of each period 
per the randomization sequences, either AB or BA (as defined in the study 
protocol. To ensure adequate distribution across 3 injection sites (ie, thigh, 
abdomen, and arm), randomization will also be stratified by injection site within 
each cohort.
Initial 
wording:
Presence of lesions, rashes, tattoos, and moles etc. on administration sites on the 
abdomen not allowing adequate conduct of injection site reaction and injection 
site injury (Synopsis and Section 7.2)
Amended 
or new 
wording:
Presence of lesions, rashes, tattoos, and moles etc. on administration sites not 
allowing adequate conduct of injection site reaction and injection site injury
Initial 
wording:
In each period, subjects will receive teduglutide administered SC to the 
abdomen either by syringe injection (syringe and vial) or pen injector. A 
different abdominal site will be used for administration in the subsequent period. 
Time of administration and administration site location will be recorded 
(Section 9.2.7)
Amended 
or new 
wording:
In each period, subjects will receive teduglutide administered SC to the arm, 
thigh or abdomen either by syringe injection (syringe and vial) or pen injector. 
The same location (ie, arm, thigh or abdomen) but a different puncture spot will 
be used for administration in the subsequent period. Time of administration and 
administration site location will be recorded.
Change 9. Minor editorial changes have been made throughout the protocol and consistency 
verbiage updates to Appendix B on male/female contraception were made to match 
Appendix D.
For non-commercial use only


Takeda
CONFIDENTIAL
Page 79
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Amendment 3
Change 1. As requested by The Food and Drug Administration, blood sampling for anti-drug 
antibody analysis is not required and has been removed from the protocol.
The following updates were made:
Section 3 (Schedule of Study Procedures) – row for immunogenicity sampling has been 
removed.
Section 9.3 (PK Samples) - Table 4 for Primary Specimen Collections, row for 
immunogenicity sample has been removed.
Section 9.3.4 (Immunogenicity) has been removed.
Change 2. As requested by The Food and Drug Administration, PK analysis is also required to 
be evaluated by injection site.
The following secondary objective was added to the Synopsis and Section 5.2.2 (Study 
Secondary Objectives):
To evaluate the bioavailability of teduglutide, by injection site (ie, thigh, abdomen, and arm), 
following the administration of a single, SC fixed dose of 3 mg or 4 mg teduglutide 
(depending upon subjects assignment in one of two cohorts as defined by body weight) 
administered via manual injection or via pen injector in healthy subjects.
The following PK endpoints were added to the Synopsis and Section 5.3.2 (Secondary 
Endpoints)
PK metrics* by injection site (ie, thigh, abdomen, and arm) including:

AUC0-tlast: Area under the concentration curve from time zero to the time of last 
measurable concentration 

Cmax: Maximum concentration

AUC0-∞: Area under the concentration curve extrapolated to infinite time
*Beginning on Day 1 of each period, PK parameters will be calculated from reliable 
teduglutide concentration-time profiles using non-compartmental methods where all 
calculations will be based on actual sampling times.
The following sentence was added to the Synopsis (Statistical Considerations) and to 
Section 11.1.3 (PK Analysis) (Third Paragraph):
“The PK endpoints will also be analyzed by injection site (ie, thigh, abdomen, and arm)”
For non-commercial use only


Takeda
CONFIDENTIAL
Page 80
TAK-633-1001 Protocol Amendment 03
Teduglutide
09 Dec 2020
Change 3. An error in the lower age range was corrected.
The correction occurred in the following section:
Section 1 (Study Summary) – Study Subject Population (First Sentence)
Initial 
wording: 
Healthy male and female subjects aged 19 – 45 years inclusive, at time of 
consent.
Amended 
or new 
wording:
Healthy male and female subjects aged 18 – 45 years inclusive, at time of 
consent.
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
NCT Number: 
NCT04465396
Study Title: 
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, 
Crossover Study to Evaluate the Bioavailability of Teduglutide Administered 
Subcutaneously by Syringe Injection Versus Pen Injector in Healthy Adult 
Subjects
Study Number: 
TAK-633-1001
SAP Version and Date: 
Final Version:   
26 Mar 2021 


1.0 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-633-1001 
CELERION STUDY NUMBER: CA29179 
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, Crossover Study to 
Evaluate the Bioavailability of Teduglutide Administered Subcutaneously by Syringe 
Injection Versus Pen Injector in Healthy Adult Subjects 
PHASE 1 
Version: Final 
Date: 26 March 2021 
Prepared by: 
, MSc 
, Data Management and Biometrics, Celerion 
, MSc 
, Clinical Pharmacology & 
Pharmacometrics, Data Management and Biometrics, Celerion 
Based on: 
Protocol Version: Amendment 3 dated 09 December 2020 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 
For non-commercial use only


TAK-633-1001
Celerion Study Number CA29179
Page 2 of 17
Statistical Analysis Plan Final
26 March 2021
CONFIDENTIAL
1.1
Approval Signatures
Electronic signature can be found on the last page of this document.
Study Title:
A Randomized, Open-label, Two-treatment, Two-period, Single-dose, 
Crossover Study to Evaluate the Bioavailability of Teduglutide 
Administered Subcutaneously by Syringe Injection Versus Pen Injector in 
Healthy Adult Subjects
Approvals:
, PhD
, Statistical and Quantitative Sciences-GI
Takeda
Date
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 3 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................6 
4.1 
Primary Objective ..........................................................................................................6 
4.2 
Secondary Objectives.....................................................................................................6 
4.3 
Study Design ..................................................................................................................6 
5.0 
ANALYSIS ENDPOINTS ..................................................................................................7 
5.1 
Primary Endpoints .........................................................................................................7 
5.2 
Secondary Endpoints .....................................................................................................7 
5.3 
Additional Endpoints .....................................................................................................7 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................8 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .......................................................8 
7.1 
General Principles ..........................................................................................................8 
7.2 
Definition of Study Days ...............................................................................................9 
7.3 
Analysis Sets ................................................................................................................10 
7.4 
Treatment Descriptions ................................................................................................10 
7.5 
Study Information ........................................................................................................10 
7.6 
Disposition of Subjects ................................................................................................11 
7.7 
Demographic and Other Baseline Characteristics .......................................................11 
7.8 
Medical History and Concurrent Medical Conditions .................................................11 
7.9 
Medication History and Concomitant Medications .....................................................11 
7.10 
Study Drug Exposure and Compliance ........................................................................12 
7.11 
Efficacy Analysis .........................................................................................................12 
7.12 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................12 
7.12.1 
Pharmacokinetic Analysis ...................................................................................12 
7.12.2 
Pharmacodynamic Analysis ................................................................................13 
7.13 
Safety Analysis ............................................................................................................13 
7.13.1 
Adverse Events ....................................................................................................14 
7.13.2 
Injection Site Reaction and Injection Site Injury Assessment .............................14 
7.13.3 
Clinical Laboratory Evaluations ..........................................................................15 
7.13.4 
Vital Signs ...........................................................................................................15 
7.13.5 
12-Lead ECGs .....................................................................................................16 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 4 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
7.13.6 
Physical Exams ....................................................................................................16 
7.13.7 
Overdose ..............................................................................................................16 
7.13.8 
Device Malfunction Assessment .........................................................................16 
7.13.9 
Other Observations Related to Safety .................................................................16 
7.14 
Interim Analysis ...........................................................................................................16 
7.15 
Preliminary Analysis ....................................................................................................16 
7.16 
Changes in the Statistical Analysis Plan ......................................................................16 
8.0 
REFERENCES ..................................................................................................................17 
 
LIST OF IN-TEXT TABLES 
Table 4:1 
Treatment Scheme for Each Cohort .........................................................................7 
Table 7:1 
Collection of Blood Samples for Pharmacokinetic Analysis .................................12 
 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 5 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC  
area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the 
last quantifiable concentration. 
 
 
 
AUClast 
area under the concentration-time curve from time 0 to time of the last quantifiable concentration 
BLQ 
below the lower limit of quantitation 
BMI 
body mass index 
CI(s) 
confidence interval(s) 
CL/F 
apparent clearance after extravascular administration, calculated using the observed value of the last 
quantifiable concentration. 
Cmax 
maximum observed concentration  
CRF 
case report form 
CRU 
clinical research unit 
CV% 
arithmetic percent coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
Geom CV% 
geometric percent coefficient of variation 
Geom Mean 
geometric mean 
GMR(s) 
geometric least-squares mean ratio(s) 
ICF 
informed consent form 
kg 
kilogram 
LSM(s) 
least-squares mean(s) 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
milligram 
n 
number of observations 
PK 
pharmacokinetic(s) 
SAE(s) 
serious adverse event(s) 
SC 
subcutaneous 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
t1/2z 
terminal disposition phase half-life 
TEAE(s) 
treatment-emergent adverse event(s) 
TFL(s) 
tables, figures, and listings 
tmax 
time of first occurrence of Cmax 
Vz/F 
apparent volume of distribution during the terminal disposition phase after extravascular administration, 
calculated using the observed value of the last quantifiable concentration. 
WHO 
World Health Organization 
z 
terminal disposition phase rate constant 
Note: The PK parameters presented in the clinical study report (CSR) and in the in-text tables will be subscripted, whereas the 
PK parameters presented in the end-of-text tables will not be subscripted. In addition, AUC  and 
z will be presented as AUCinf 
and Lambdaz in the end-of-text tables, respectively. 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 6 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
4.0 
OBJECTIVES 
4.1 
Primary Objective 
To evaluate the bioavailability of teduglutide following the administration of a single 
subcutaneous (SC) fixed dose of 3 mg or 4 mg teduglutide (depending upon subjects assignment 
in one of two cohorts as defined by body weight) administered via manual injection or via pen 
injector in healthy subjects. 
4.2 
Secondary Objectives 
To evaluate the bioavailability of teduglutide, by injection site (ie, thigh, abdomen, and arm), 
following the administration of a single SC fixed dose of 3 mg or 4 mg teduglutide (depending 
upon subjects assignment in one of two cohorts as defined by body weight) administered via 
manual injection or pen injector in healthy subjects. 
To evaluate other PK parameters of teduglutide, as appropriate, following the administration of a 
single dose of teduglutide administered via manual injection or pen injector in healthy subjects.  
To assess the safety and tolerability of SC injections of teduglutide in healthy subjects. 
To assess the safety and performance of the pen injector for SC drug administration in healthy 
subjects. 
4.3 
Study Design 
This is a randomized, open-label, two-treatment, two-period, two-sequence, single dose, 
crossover bioavailability study in healthy adult subjects. 
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dosing.  
 kg 
[Cohort 1] and >75.0 
cohort, subjects will be admitted to the 
clinical facility the day prior to each dosing and will be confined at least 24 hours; subjects will 
be released following completion of the 24-hour study procedures in each period. On Day 1 of 
Period 1, subjects in each cohort will be randomized to 1 of 2 treatment sequences as indicated in 
Table 4:1 below. Fixed teduglutide doses (delivered by pen injector or from approved single-use 
vials) is 3 mg for subjects in Cohort 1 and 4 mg for subjects in Cohort 2. Each dose will be 
separated by a washout period of 7 days. Blood samples for teduglutide PK will be collected 
predose and for 24 hours following each teduglutide dose.  
 
 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 7 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
Table 4:1 
Treatment Scheme for Each Cohort 
Weightband 
Cohort / Dose level 
No. of 
Subjects 
Sequence* 
Treatment  
Period 1 
(Day 1) 
Washout 
Period 
(7 days) 
Treatment  
Period 2 
Day 1) 
 kg - 
 kg 
Cohort 1 / 3mg 
n=16 
AB 
Reference 
(fixed dose by  
vial and syringe)** 
 
Test 
(fixed dose by  
pen injector)** 
>75.0 kg - 
 kg 
Cohort 2 / 4mg 
n=16 
- 
 kg 
Cohort 1 / 3mg 
n=16 
BA 
Test 
(fixed dose by  
pen injector)** 
 
Reference 
(fixed dose by  
vial and syringe)** 
>75.0 kg - 
 
Cohort 2 / 4mg 
n=16 
* To ensure adequate distribution across 3 injection sites (ie, thigh, abdomen, and arm), randomization will be stratified by injection site 
within each cohort. 
**Fixed teduglutide doses (delivered by pen injector or from approved single-
 kg - 
 kg) 
and 4mg for subjects in Cohort 2 (>75.0 kg - 
 
Treatment A: Teduglutide administered by syringe injection  
Treatment B: Teduglutide administered by pen injector 
Safety and tolerability will be assessed by treatment-emergent adverse events (TEAEs), 
including injection site reaction and injection site injury assessments, clinical laboratory 
evaluations, physical examinations, and vital signs. 
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will be contacted by the clinical research unit (CRU) 7 (±2) days after the last study 
drug administration to determine if any AE has occurred since the last study visit. 
5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoints 
 PK parameters:  AUClast, Cmax, and AUC  
5.2 
Secondary Endpoints  
 PK parameters:  AUClast, Cmax, and AUC  by injection site (ie, thigh, abdomen, and arm) 
 PK parameters:  tmax, 
z, t1/2z, CL/F, and Vz/F 
 Occurrence of TEAEs, including injection site reactions and injection site injury assessments. 
 Routine clinical safety monitoring that includes: vital signs, clinical laboratory test results 
(hematology, serum chemistry, coagulation (as appropriate), and urinalysis) and physical 
examinations. 
 Occurrence of device malfunctions. 
5.3 
Additional Endpoints 
 
 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 8 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
The overall power for the endpoints (AUClast, AUC , and Cmax) with a total sample size of 
64 subjects (32 subjects per cohort) will be 92.6% power based on a 5% type 1 error and a 
Coefficient of Variation of 21%, assuming a true ratio of test/reference of 1.0 in their relative 
bioavailabilities based on the acceptance interval of 80.00 to 125.00%, for this statistical 
comparison of each cohort. The sample size of 28 subjects within each cohort (14 each sequence) 
was accounted for approximately 10% potential drop-outs and/or non-evaluable concentration 
time-profiles to yield 32 subjects per cohort (16 subjects per sequence within each cohort). This 
sample size was calculated with SAS® v9.4. 
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
All PK analyses will be conducted using Phoenix® WinNonLin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4, or higher. All data recorded on the 
case report form (CRF) will be listed by subject. All tables, figures, and listings (TFLs) shells 
and numbering list will be included and specified in the TFL Shells document. 
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (Geom Mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD), 25th and 75th quantiles, 
and standard error of the mean (SEM) will be presented to 2 more levels of precision than the 
individual values. Minimum and maximum values will be presented to the same precision as the 
individual values. Arithmetic percent coefficient of variation (CV%) and geometric percent 
coefficient of variation (Geom CV%) will be presented to 1 decimal place.  
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) 
around the ratio will be reported using 2 decimal places.  
Concentration values below the lower 
the concentration table listings and footnoted accordingly. BLQ values will be treated as zero for 
the calculation of summary statistics, the generation of concentration plots, and the calculation of 
PK parameters, unless they are obvious outliers (eg, BLQ value between measurable values), in 
which case they will be treated as missing. 
and inferential (analysis of variance [ANOVA]) statistics if one or more of the following criteria 
are met:  
 
value in that period  
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 9 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
 A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist) 
 A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist) 
The details on PK parameter calculations and TFLs will be outlined in the Clinical 
Pharmacology Analysis Plan and TFL Shell document including specifics on the following: 
 Insufficient data to determine a reliable t1/2z value and other terminal disposition phase rate 
constant (
z)-dependent parameters 
 PK parameters presented by cohort and treatment, including the units, precision, and 
summary statistics that will be presented in in-text and end-of-text tables 
 Concentration data presented by cohort and treatment, including the units, precision, and 
summary statistics that will be presented in end-of-text tables 
 Concentration data file used for PK analysis 
 PK parameter WinNonlin® output file used to generate the TFLs 
 ANOVA results presented in in-text and end-of-text table(s).  
 Concentration-time data will be plotted on linear and semi-log scales 
 Concentration versus time figures for individual subjects presented in Appendix 16.2.6 of the 
CSR. 
For demographic and safety data where appropriate, variables will be summarized descriptively. 
For the categorical variables, the count and proportions of each possible value will be tabulated, 
where applicable. The denominator for the proportion will be based on the number of subjects 
who provided non missing responses to the categorical variable. For continuous variables, the 
number of subjects with non-missing values, mean, SD, minimum, median, and maximum values 
will be tabulated. The level of precision will be presented as follows: minimum/maximum in the 
same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. Counts and percentages will be presented as integers. 
7.2 
Definition of Study Days 
Day 1 for each period is defined as the date on which a subject is administered their first dose of 
the study drug(s) in each period. Other study days are defined relative to Day 1 with Day -1 
being the day prior to Day 1 of each period. Study day prior to the first dose of each treatment 
will be generated as: date of assessment-date of first dose in each period; study day on or after 
the date of first dose will be generated as: date of assessment-date of first dose in each period +1. 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 10 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
7.3 
Analysis Sets 
PK Set:  All subjects who receive at least one dose of the study drug and have at least 
1 quantifiable plasma concentration. All available data will be listed/included in the 
concentration and PK parameter tables to the extent possible. 
PK Evaluable Set:  A subset of the PK set; all subjects who comply sufficiently with the protocol 
and display an evaluable PK profile from which to calculate reliable estimates of the PK 
parameters (eg., exposure to treatment, availability of measurements in both periods, absence of 
major protocol violations or events with potential to affect the PK concentrations [eg., emesis], 
and absence of significant carryover [eg., predose concentration >5% Cmax). This set will be used 
for the concentration summaries and mean figures, PK parameter summaries, and statistical 
analyses on relative bioavailability of treatments. Any subject or data excluded from the analysis 
will be identified, along with their reason for exclusion, in the CSR. 
Safety Set: All subjects who received at least one dose of the study drug will be included in the 
safety evaluations. 
7.4 
Treatment Descriptions 
Each cohort will receive two treatments.  
 
For Cohort 1, treatments will be:  
Treatment A1: a single subcutaneous dose of 3 mg teduglutide administered by syringe injection 
(Cohort 1) 
Treatment B1: a single subcutaneous dose of 3 mg teduglutide administered by pen injector 
(Cohort 1) 
 
For Cohort 2, treatments will be:  
Treatment A2: a single subcutaneous dose of 4 mg teduglutide administered by syringe injection 
(Cohort 2) 
Treatment B2: a single subcutaneous dose of 4 mg teduglutide administered by pen injector 
(Cohort 2) 
 
Note: Treatments A1, B1, A2, and B2 may be labelled as 3 mg teduglutide (syringe injection), 
3 mg teduglutide (pen injector), 4 mg teduglutide (syringe injection), and 4 mg teduglutide (pen 
injector), respectively, in the TFLs.   
7.5 
Study Information 
signed informed consent form, date of first dose, date of last dose, date of 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 11 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Dictionary, and SAS version used for creating the datasets. 
7.6 
Disposition of Subjects 
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized by randomized treatment sequence 
and overall for each cohort. Randomized treatment sequence, and disposition information will be 
listed by subject.  
7.7 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by randomized 
treatment sequence and overall for each cohort. Summary statistics (n, mean, SD, minimum, 
median, and maximum) will be generated for continuous variables (age [recorded in the CRF], 
weight, height and body mass index [BMI]) and the number and percentage of subjects within 
each category will be presented for categorical variables (sex, race, and ethnicity). Height, 
weight, and BMI recorded at screening will be used in the baseline summaries. Demographics 
data will also be listed as recorded on the CRF, including the date of informed consent. 
7.8 
Medical History and Concurrent Medical Conditions 
Medical history will be obtained, including any significant conditions or diseases relevant to the 
disease under study that resolved at or before signing the informed consent form (ICF). 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing the ICF.  
condition started after taking the study drug(s) will be classified as an adverse event. All medical 
history may be coded using the Medical Dictionary for Regulatory Activities (MedDRA® ), as 
described in the Data Management Plan (DMP). The medical history listing will include whether 
the event was medical or surgical, the body system or organ class involved, coded term, start 
date (if known) and end date or whether the condition was ongoing, and a description of the 
condition or event. There will be no analysis of medical history. 
7.9 
Medication History and Concomitant Medications 
Medication history to be obtained includes any medication relevant to eligibility criteria and 
safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant medication 
includes any medication other than study drug taken at any time between time of signing the ICF 
through the end of the study (including follow-up visit). All medication history and concomitant 
medications recorded during the study will be coded with the WHO Dictionary, as described in 
the DMP, and listed. If appropriate, the listing will include the medication name, coded term, 
dosage, route of administration, start date and time (if known), end date and time, or whether it 
continued after study completion, and indication for use. 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 12 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
7.10 
Study Drug Exposure and Compliance 
The date, time, administration site, treatment (pen injector or syringe), and dosage of each 
teduglutide dose will be listed by subject. 
7.11 
Efficacy Analysis 
Not applicable. 
7.12 
Pharmacokinetic/Pharmacodynamic Analysis 
7.12.1 
Pharmacokinetic Analysis 
Blood samples for the assessment of plasma teduglutide concentrations will be collected as 
outlined in Table 7:1 
Table 7:1 
Collection of Blood Samples for Pharmacokinetic Analysis 
Analyte 
Matrix 
Period 
Scheduled Time (Hours)* 
Teduglutide 
Plasma 
1 and 2 
Predose, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours postdose
*The actual date and time of sample collection will be recorded on the source document in the case report form. 
Concentration data at each time point will be summarized by cohort and treatment using the 
following descriptive statistics: n, mean, SD, CV%, SEM, minimum, median, maximum, and 
25th and 75th quantiles. Excluded concentrations will be presented and footnoted as such in the 
concentration table listings, and those values will be excluded from the calculation of descriptive 
statistics.  
Individual concentration-time curves will be presented in linear/linear and log/linear scale. 
Figures showing the mean (with ±SD as error bars) as well as the median (with 25th and 75th 
quantile bars) concentration time profiles will be also presented in linear/linear and log/linear 
scale. 
PK parameters will be calculated from evaluable teduglutide concentration-time profiles using 
non-compartmental methods where all calculations will be based on actual sampling times. PK 
parameters will be summarized by cohort, treatment, and injection site (ie, thigh, abdomen, and 
arm), using the following descriptive statistics: n, Mean, SD, CV%, SEM, minimum, median, 
maximum, Geom Mean, and Geom CV%. Excluded parameters will be presented and footnoted 
as such in the PK parameter table listings, and those values will be excluded from the calculation 
of descriptive statistics. 
Statistical analysis of PK data will be based on the PK Evaluable Set. PK parameters AUClast, 
AUC , and Cmax, will be analyzed using an ANOVA model for each cohort separately. PK 
parameters will be transformed prior to analysis using a logarithmic transformation. The 
difference in means and the corresponding two-sided 90% CI on the log-transformed scale will 
be obtained from that model. The difference in means and the corresponding CI will be 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 13 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
back-transformed to obtain the ratio of geometric means and the corresponding two-sided 90% 
CI for the ratio on the original scale. The terms used in the ANOVA model will be sequence, 
subject within sequence, period and treatment. According to EMA Guideline on the Investigation 
of Bioequivalence (EMA Guideline on the Investigation of Bioequivalence, 
CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, London, 20 January 2010.), subjects who will not 
provide evaluable data for both periods will be excluded and fixed effects will be used for all 
terms. 
To assess bioavailability between test (pen injector) and reference (syringe injection), the 90% 
CI for the ratio of geometric means for PK metrics, AUClast, AUC , and Cmax will be derived and 
compared (and would be contained within the acceptance interval of 80.00 to 125.00% if 
bioequivalent). 
The comparison of interest is as follows: 
 Pen injector (Treatment B1) compared to syringe injection (Treatment A1) (Cohort 1) 
 Pen injector (Treatment B2) compared to syringe injection (Treatment A2) (Cohort 2) 
 
The following SAS code will be used to run the analysis in each cohort separately:  
 
PROC MIXED DATA=XXXX; 
CLASS Treatment Subject Period Sequence; 
MODEL <PK_Parameter> = Treatment Period Sequence Subject(sequence) / DDFM=KR; 
-1 1 / CL ALPHA = 0.10 E; 
LSMEANS Treatment; 
Run; 
 
7.12.2 
Pharmacodynamic Analysis 
Not applicable. 
7.13 
Safety Analysis 
For each cohort, safety will be evaluated by the incidence of TEAEs (including injection site 
reactions and injection site injuries), severity and type of TEAEs, summary of device 
malfunction (pen injector), 
aboratory results and 
vital signs using the Safety Set. All clinical safety data will be listed by subject and assessment 
time points, including rechecks, unscheduled assessments, and early termination, 
chronologically.  
Where individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. 
 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 14 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
7.13.1 
Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to study drug (related or not 
related) and action relative to the study drug as recorded in the CRF. Study procedure taken due 
to AE will also be listed. All AEs occurring during this study will be coded using the MedDRA®, 
as described in the DMP. However, only TEAEs occurring after administration of the first dose 
of study drug and through the end of the study (approximately 7 (± 2) days after the last dose of 
study drug administration) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study drug 
administration.  
For each cohort and treatment, TEAEs (including injection site reactions and injection site 
injuries recorded as AEs) will be coded using MedDRA® and tabulated by System Organ Class 
(SOC) and Preferred Term. Summary tables will include number of subjects reporting the AE 
and as percent of Safety Set by treatment and overall. The most commonly reported non-serious 
TEAEs (i.e., those events reported by >5% of all subjects in each treatment, excluding serious 
adverse events [SAEs]) will also be summarized. For the list of all AE summary table see TFL 
Shells. 
In addition, TEAEs will be summarized as number of AEs and percentage of AEs for each 
treatment for the overview of TEAEs.  
 
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a subject has multiple AEs with different severity levels within the same term, the subject will be 
counted in the most severe category only. For each relationship to study drug, if a subject has 
both related and unrelated AEs with the same term, the subject will be counted as having related 
TEAEs. 
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAE. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the CSR. 
7.13.2 
Injection Site Reaction and Injection Site Injury Assessment 
Local tolerability, reactions, and injuries at the injection site will be evaluated by the 
investigator/designee prior to dosing, 2 minutes after dosing, and 0.5 1, 2, 4, 6, 8, 12, and 24 
hours postdose in each period. 
Additionally, subjects will be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, injection site pain, redness, bruising, and/or swelling, etc, that may represent 
an administration-related reaction or injury to the study medication or administration method. 
Subjects will be asked to report AEs to the CRU staff immediately as they are experienced. 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 15 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
Appropriate treatment and follow-up will be determined by the investigator. Any injection site 
reaction or injury will be collected and graded as mild, moderate, or severe. 
All injection site reaction and injection injury assessment data recorded in the CRF will be listed 
by cohort, subject, and treatment. Injection site reactions and injection injuries recorded as AEs 
will be included in the TEAE summaries. 
7.13.3 
Clinical Laboratory Evaluations 
Serum chemistry, hematology, coagulation (as appropriate) and urinalysis will be performed at 
screening, check-in (Day -1) of each period, 24 hours postdose of each period or prior to early 
termination from the study. In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the investigator. 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by cohort, treatment and time point of 
collection. Change from baseline will be summarized. Baseline is defined as the last assessment 
including rechecks taken prior to dosing in each period (Day -1 Check-in).  
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
baseline (above normal (H), normal (N), or below normal (L)) with those postdose time points. 
For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range values and 
corresponding recheck results will be listed.  
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a computer clinically significant (CS) range. If the value falls 
within the computer 
ly significant. If the value 
fails the computer CS ran
investigator to 
determine how the out-of-range value should be followed using 4 Investigator flags: "N", not 
clinically significant, "R", requesting a recheck, "^", checking at the next scheduled visit, or "Y", 
clinically significant. All clinically significant laboratory tests, as indicated by the investigator, 
and the corresponding values will be listed by subject. All clinical laboratory data will be 
presented in by-subject data listings. 
7.13.4 
Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure (systolic and 
diastolic), and heart rate, will be obtained at screening, predose, and at 2 and 24 hours postdose 
in each period or upon early termination. Additional unscheduled vital signs measurements may 
be taken at other times, if deemed necessary by the investigator. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results and change from baseline by cohort, treatment and time point of collection. Baseline 
is defined as the last assessment, including rechecks, taken prior to dosing (predose) in each 
treatment. Vital signs will also be displayed in a data listing by subject. 
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 16 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
7.13.5 
12-Lead ECGs 
Single12-lead ECGs will be recorded at screening. Additional unscheduled ECGs may be 
recorded at other times if deemed necessary by the investigator. All ECG data collected during 
the study will be displayed in a data listing by subject. No summaries will be provided for ECG 
data.  
7.13.6 
Physical Exams 
A full physical examination will be performed at screening and prior to discharge in Period 2, or 
upon early termination. An abbreviated physical examination will be performed at check-in for 
each period and prior to release at Period 1. Symptom driven physical exams may be performed 
at other times at the discretion of the investigator. Physical exam findings will be presented in a 
data listing by subject. Reproductive system findings will also be listed by subject. 
7.13.7 
Overdose  
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs.  
7.13.8 
Device Malfunction Assessment  
A device malfunction assessment will be performed on the pen injector during preparation, 
immediately prior, and post teduglutide administration. All device malfunction assessment data, 
as recorded on the CRF, will be listed by subject and summarized by cohort using the number 
and percentage of events.  
7.13.9 
Other Observations Related to Safety 
Not applicable.  
7.14 
Interim Analysis 
Not applicable.  
7.15 
Preliminary Analysis 
Analysis will be completed as described in the CPAP and Section 7.12.1 of the SAP, with the 
following changes: 1) QCed data will be used (not QAed); 2) nominal times will be used for the 
calculation of PK parameters (not actual sampling times); 3) tables and figures will be created 
using Phoenix® WinNonlin® Version 8.1 or higher. 
7.16 
Changes in the Statistical Analysis Plan  
The analyses described in this statistical analysis plan do not differ from those specified in the 
protocol.  
For non-commercial use only


 
TAK-633-1001 
Celerion Study Number CA29179 
 
 
 
Page 17 of 17
Statistical Analysis Plan Final 
26 March 2021
 
CONFIDENTIAL 
8.0 
REFERENCES 
EMA Guideline on the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 
Rev. 1/Corr**, London, 20 January 2010. 
For non-commercial use only