Clinical trial NCT03268941
Conditions: Diabetes Mellitus and Gastroparesis, Idiopathic Gastroparesis
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2017-09-26; Completion date: 2018-03-09
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, PK and PD of TAK-906 in participants with Gastroparesis (GP).

Detailed description:
The drug being tested in this study is called TAK-906 maleate. TAK-906 maleate is being tested to treat people who have DG or IG. This study will assess the safety, tolerability, PK/PD and food effect of TAK-906 and will determine the effect of TAK-906 on gastric emptying (GE).

The study enrolled a total of 51 participants. This study will be conducted in two parts: Part 1 and Part 2. Part 1 will consist of 48 participants enrolled in 3 active treatment groups and 1 placebo group. Participants in Part 1 will be randomly assigned (by chance, like flipping a coin) to one of the 3 active treatment groups or 1 placebo group-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK 906 maleate 5 mg
* TAK 906 maleate 25 mg
* TAK 906 maleate 100 mg
* Placebo

All participants who will complete Part 1 of the study will be eligible for enrollment in Part 2. Part 2 consisted of 21 participants who completed Part 1 and were assigned to the 2 open-label treatment groups as follow:

* TAK-906 maleate 25 mg Fed + TAK-906 maleate 25 mg Fasted: crossover design, with a minimum 7-day washout in doses of each period.
* Metoclopramide 10 mg

This multi-center trial will be conducted the United States. The overall time to participate in this study is approximately 8 weeks. Participants will make a final visit to the clinic 10-14 days after receiving their last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-906 placebo-matching (4x0 mg), capsule, orally, twice daily (BID) on Days 1-8 and once on Day 9 under fasted conditions. arm 2: TAK-906 maleate 1x5 mg, capsule, orally, BID and TAK-906 maleate placebo-matching (3x0 mg), capsules, orally, BID on Days 1-8, followed by TAK-906 maleate 1x5 mg, capsule, orally once on Day 9 under fasted conditions. arm 3: TAK-906 maleate 1x25 mg, capsule, orally, BID and TAK-906 maleate placebo-matching (3x0 mg), capsules, orally, BID on Days 1-8 followed by TAK-906 maleate 1x25 mg, capsule, orally, once on Day 9 under fasted conditions. arm 4: TAK-906 maleate 100 mg (4x25 mg), capsules, orally, BID on Days 1-8 and once a day on Day 9 under fasted conditions. arm 5: TAK-906 maleate 1x25 mg, capsule, orally, once on Day 1 of Period 1 under fed conditions (high fat breakfast), followed by a minimum 7- day washout. arm 6: TAK-906 maleate 1x25 mg, capsule, orally, once on Day 1 of Period 2 under fasted conditions. arm 7: Metaclopramide 10 mg, tablet, orally, once, 1 hour prior to breakfast on Day 1 in Part 2.
Interventions: intervention 1: TAK-906 Maleate intervention 2: Metaclopramide intervention 3: TAK-906 Maleate Placebo
Intervention descriptions: intervention 1: TAK-906 Maleate Capsules intervention 2: Metaclopramide Tablets intervention 3: TAK-906 placebo-matching Capsules

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A 2-Part, Randomized, Double-Blind and Open-Label, Placebo and 
Active-Comparator Controlled Trial to Evaluate the Safety, Pharmacokinetics and 
Pharmacodynamics for TAK-906 in Subjects With Diabetes Mellitus and Gastroparesis or With 
Idiopathic Gastroparesis
NCT Number: NCT03268941
Protocol Approve Date: 14 December 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
TAK-906-1002: A 2-Part, Randomized, Double-Blind and Open-Label, Placebo and 
Active-Comparator Controlled Trial to Evaluate the Safety, Pharmacokinetics and 
Pharmacodynamics for TAK-906 in Subjects With Diabetes Mellitus and Gastroparesis or With 
Idiopathic Gastroparesis
Study Identifier:
TAK-906-1002
Compound:
TAK-906 maleate
Version/Amendment 
Number:
04
Date: 
14 December 2017
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
23 May 2017
Initial version
Not applicable
Global
27 June 2017 
01
Nonsubstantial
Global
05 September 2017
02
Nonsubstantial
Global
11 December 2017
03
Nonsubstantial
Global
14 December 2017
04
Nonsubstantial
Global
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.


TAK-906
Study No. TAK-906-1002
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CONFIDENTIAL
TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................6
1.1
Protocol Amendment No. 04 Summary of Changes ...................................................9
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................11
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.2
Rationale for the Proposed Trial...............................................................................17
4.3
Benefit/Risk Profile .................................................................................................17
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................18
5.1
Hypotheses ..............................................................................................................18
5.2
Trial Objectives .......................................................................................................18
5.2.1
Trial Primary Objective......................................................................................18
5.2.2
Trial Secondary Objectives ................................................................................18
5.2.3
Trial Exploratory Objectives ..............................................................................18
5.3
Endpoints.................................................................................................................19
5.3.1
Primary Safety Endpoint ....................................................................................19
5.3.2
Secondary Endpoints..........................................................................................19
5.3.3
Exploratory Endpoints .......................................................................................19
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................20
6.1
Trial Design.............................................................................................................20
6.1.1
Part 1 .................................................................................................................20
6.1.2
Part 2 .................................................................................................................21
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................22
6.2.1
Rationale of Trial Design ...................................................................................22
6.2.2
Rationale for Dose .............................................................................................22
6.2.3
Rationale for Endpoints......................................................................................23
6.2.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................24
6.3
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................24
6.4
Trial Beginning and End/Completion.......................................................................25
6.4.1
Definition of Beginning of the Trial ...................................................................25
6.4.2
Definition of End of the Trial.............................................................................25
6.4.3
Definition of Trial Discontinuation ....................................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27


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Study No. TAK-906-1002
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CONFIDENTIAL
7.1
Inclusion Criteria .....................................................................................................27
7.2
Exclusion Criteria ....................................................................................................28
7.3
Excluded Medications, Supplements, Dietary Products............................................30
7.3.1
Prohibited Medications ......................................................................................30
7.3.2
Permitted Medications .......................................................................................31
7.4
Diet, Fluid, Activity.................................................................................................32
7.4.1
Diet and Fluid ....................................................................................................32
7.4.2
Activity..............................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................35
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................36
7.7
Subject Replacement................................................................................................36
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................37
8.1
Clinical Trial Drug...................................................................................................37
8.1.1
Trial Drugs.........................................................................................................37
8.1.2
Use of Rescue Medication..................................................................................37
8.1.3
Clinical Study Drug Labeling.............................................................................38
8.1.4
Clinical Study Drug Inventory and Storage ........................................................38
8.1.5
Clinical Study Drug Blinding.............................................................................38
8.1.6
Randomization Code Creation and Storage ........................................................38
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................38
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs...............................38
8.1.9
Ancillary Supplies..............................................................................................39
9.0
TRIAL PROCEDURES.................................................................................................40
9.1
Administrative Procedures.......................................................................................40
9.1.1
Informed Consent Procedure..............................................................................40
9.1.2
Inclusion and Exclusion .....................................................................................40
9.1.3
Medical History, Prior and Concomitant Medications, and Demographics .........41
9.2
Clinical Procedures and Assessments.......................................................................41
9.2.1
Physical Examinations .......................................................................................41
9.2.2
Height and Weight .............................................................................................41
9.2.3
BMI ...................................................................................................................41
9.2.4
Vital Sign Measurement.....................................................................................41
9.2.5
12-Lead ECG.....................................................................................................41
9.2.6
Trial Drug Administration..................................................................................42
9.2.7
AE Monitoring...................................................................................................43


TAK-906
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CONFIDENTIAL
9.2.8
Laboratory Procedures and Assessments ............................................................43
9.2.9
Symptom Assessments.......................................................................................44
9.3
PK, PD, and Pharmacogenetic Samples ...................................................................45
9.3.1
PK Measurements..............................................................................................45
9.3.2
PD Measurements..............................................................................................46
9.3.3
PGx....................................................................................................................47
9.4
Confinement ............................................................................................................47
10.0
ADVERSE EVENTS ....................................................................................................48
10.1
Definitions and Elements of AEs .............................................................................48
10.1.1 SAEs..................................................................................................................50
10.2
AE Procedures.........................................................................................................51
10.2.1 Assigning Severity/Intensity of AEs...................................................................51
10.2.2 Assigning Causality of AEs................................................................................52
10.2.3 Start Date...........................................................................................................52
10.2.4 End Date............................................................................................................52
10.2.5 Pattern of AE (Frequency) .................................................................................52
10.2.6 Action Taken With Study Treatment..................................................................52
10.2.7 Outcome ............................................................................................................52
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................53
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....55
11.0
STATISTICAL METHODS..........................................................................................56
11.1
Statistical and Analytical Plans ................................................................................56
11.1.1 Analysis Sets......................................................................................................56
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................56
11.1.3 PK Analysis .......................................................................................................57
11.1.4 PD Analysis .......................................................................................................57
11.1.5 Safety Analysis ..................................................................................................57
11.2
Interim Analysis and Criteria for Early Termination ................................................58
11.3
Determination of Sample Size..................................................................................58
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
12.1
Study-Site Monitoring Visits ...................................................................................59
12.2
Protocol Deviations..................................................................................................59
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
13.1
IRB and/or IEC Approval ........................................................................................60


TAK-906
Study No. TAK-906-1002
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CONFIDENTIAL
13.2
Subject Information, Informed Consent, and Subject Authorization .........................61
13.3
Subject Confidentiality ............................................................................................62
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................62
13.4.1 Publication and Disclosure.................................................................................62
13.4.2 Clinical Trial Registration..................................................................................63
13.4.3 Clinical Trial Results Disclosure ........................................................................63
13.5
Insurance and Compensation for Injury....................................................................63
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................64
14.1
Administrative Information......................................................................................64
14.1.1 Study Contact Information .................................................................................64
14.1.2 INVESTIGATOR AGREEMENT......................................................................65
14.1.3 Study-Related Responsibilities...........................................................................66
14.1.4 List of Abbreviations .........................................................................................67
15.0
DATA HANDLING AND RECORDKEEPING............................................................69
15.1
CRFs (Electronic and Paper)....................................................................................69
15.2
Record Retention .....................................................................................................69
16.0
REFERENCES..............................................................................................................71
17.0
APPENDICES...............................................................................................................72
LIST OF IN-TEXT TABLES
Table 6.a
Doses for Part 1 .................................................................................................20
Table 6.b
Doses for Part 2 .................................................................................................22
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................32
Table 7.b
Timing of Meals Relative to Dosing and Procedures ..........................................34
Table 9.a
Primary Specimen Collections ...........................................................................45
Table 10.a
Takeda Medically Significant AE List................................................................51
LIST OF APPENDICES
Appendix A
Detailed Description of Amendments to Text.....................................................72
Appendix B
Responsibilities of the Investigator.....................................................................73
Appendix C
Elements of the Subject Informed Consent.........................................................75
Appendix D
Investigator Consent to the Use of Personal Information ....................................78
Appendix E
Pregnancy and Contraception.............................................................................79


TAK-906
Study No. TAK-906-1002
Page 6 of 82
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CONFIDENTIAL
1.0
TRIAL SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. (Takeda Global Research and 
Development –United States)
Compound:
TAK-906 maleate
Study Identifier: TAK-906-1002
Phase: 2a
Protocol Title: TAK-906-1002: A 2-Part, Randomized, Double-Blind and Open-Label, Placebo and 
Active-Comparator Controlled Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics for TAK-906 
in Subjects With Diabetes Mellitus and Gastroparesis or With Idiopathic Gastroparesis
Trial Design:
This is a randomized, double blind and open-label, placebo and active-comparator controlled trial to evaluate the 
safety, pharmacokinetics (PK), and pharmacodynamics (PD) for TAK-906 in subjects with diabetes mellitus and 
gastroparesis (DG), or idiopathic gastroparesis (IG). The trial will consist of 2 parts and is designed to allow all 
enrolled subjects to participate in each part of the study, at the discretion of the investigator. Subjects may decline 
participation at any time during the study. 
In Part 1, approximately 48 subjects will be randomized into 1 of 3 active treatment arms (ie, orally [PO] TAK-906 
maleate 5 mg twice daily [BID], 25 mg BID or 100 mg BID) or a matching placebo BID arm in a double-dummy 
manner for 9 consecutive days, for a total of 17 doses (ie, BID Days 1 to 8 and morning dose on Day 9). All trial drug 
dosing will be under fasted conditions. Gastrointestinal (GI) emptying will be evaluated following a test meal using a 
13C-Spirulina gastric emptying breath test (GEBT), and GI emptying and motility will also be evaluated using 
SmartPill technology. Blood samples for assessment of TAK-906 concentrations will be collected at scheduled time 
points from predose on Day 1 to 48 hours after Day 7 dose. Blood samples for assessment of prolactin concentrations 
in serum will be collected at Screening and scheduled time points from Day -2 to 48 hours after Day 7 dose. Subject 
randomization will be stratified by the underlying condition, ie, DG versus IG.
Approximately 18 subjects who completed Part 1 of the study (and following a minimum 7-day washout from the last 
dose in Part 1) will be enrolled into Part 2 of the study. At the discretion of the investigator approximately 6 subjects 
will receive TAK-906 maleate 25 mg with and without food in an open-label crossover design over 2 periods (ie, fed, 
fasted). Blood samples for assessment of TAK 906 concentrations will be collected from predose to 48 hours after 
each dose of TAK-906 maleate. Furthermore, up to an additional 12 subjects who completed Part 1 of the study will be 
enrolled at the discretion of the investigator to participate in the evaluation of TAK-906 vs active comparator 
metoclopramide to confirm the responsiveness of the GEBT test. Subject will be blinded to treatment until all subjects 
have completed Part 1. Blood samples for assessment of TAK-906 or metoclopramide concentrations will be collected 
at scheduled time points from predose on Day 1 to 48 hours postdose.
Key safety and tolerability will be assessed during Parts 1 and 2 through physical examinations, vital signs, 12-lead 
electrocardiogram (ECG), and clinical laboratory assessments, as well as collection of serious and nonserious adverse 
events (AEs). 
After completion of the trial (or following subject withdrawal), all subjects will return for a Follow-up Visit 10 to 
14 days after their last dose of study medication.
Trial Primary Objective:

To evaluate safety and tolerability of TAK-906 in subjects with gastroparesis (GP).
Trial Secondary Objectives:

To assess the prolactin PK/PD relationship in subjects with GP.

To demonstrate the effect of TAK-906 on GEBT. 
Trial Subject Population: Male and female subjects aged 18 to 75 years, inclusive, with DG or IG.


TAK-906
Study No. TAK-906-1002
Page 7 of 82
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CONFIDENTIAL
Planned Number of Subjects:
Part 1: 48
Part 2: 18
Planned Number of Sites:
The study is being conducted at multiple sites in the United 
States
Dose Levels:
Part 1
TAK-906 maleate 5 mg BID
TAK-906 maleate 25 mg BID
TAK-906 maleate 100 mg BID
matching placebo BID
Part 2:
TAK-906 maleate 25 mg once daily (QD)
Metoclopramide 10 mg QD
Route of Administration:
PO
Duration of Treatment:
Part 1: 9 days (ie, Days 1-8 BID; Day 9 QD in am)
Part 2: 8 days (single dose fed and fasted with 7-day 
washout between doses)
Part 2: 3 days (metoclopramide)
Planned Trial Duration:
Approximately 8 Weeks 
Main Criteria for Inclusion:
Male and female subjects aged 18 to 75 years, inclusive, diagnosed with documented slow gastric emptying (GE) and 
a minimum of 3-month history of symptoms consistent with GP, which may include: postprandial fullness or nausea, 
vomiting, abdominal pain, loss of appetite, and early satiety.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
1.
Subjects who have a history of clinically significant endocrine (apart from diabetes mellitus), GI (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, 
respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases 
will be excluded from the trial.
2.
Has acute severe gastroenteritis and pronounced dehydration in the 48 hours prior to Screening, gastric 
pacemaker, chronic parenteral feeding or persistent severe vomiting.
3.
Has a known disturbance of small intestinal absorption, exocrine pancreatic function liver metabolism, and 
pulmonary function.
4.
Has a history of anorexia nervosa or bulimia.
5.
Has a history of additional risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, family history of 
Long QT Syndrome), evidence of cardiac autonomic neuropathy, eg, lack of respiratory rate variation upon deep 
breathing.
6.
Previous history of bezoars (the presence of retained liquid, bile, or small amounts of poorly organized food 
residue is permitted).
7.
Difficulty swallowing solid food or pills.
8.
Prior surgery involving the luminal gastrointestinal tract (cholecystectomy, appendectomy, and hysterectomy are 
permitted if performed >3 months prior to SmartPill test).
9.
Any abdominal or pelvic surgery within the past 3 months.
10. Known or history of inflammatory bowel disease.
11. Has active diverticulitis, diverticular stricture, and other intestinal strictures.
12. Lactating or pregnant women as determined by positive serum β-human chorionic gonadotropin (hCG) test at 
Screening and within 24 hours of the first dose. 


TAK-906
Study No. TAK-906-1002
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CONFIDENTIAL
Main Criteria for Evaluation and Analyses:
The primary safety endpoint of the study is key safety and tolerability as assessed through physical examinations, vital 
signs, ECG, and laboratory assessments as well as collection of serious and nonserious AEs. The following secondary 
endpoints will be assessed through evaluation of the following parameters: 
!
The change in serum prolactin from Baseline to Day 1 at time of first occurrence of maximum plasma 
concentration (tmax) for TAK-906 following administration with TAK-906 maleate vs placebo.
!
The change from Baseline to Day 7 in GEBT gastric half-emptying time as measured by the 13C Spirulina GEBT 
following a multiple doses of TAK-906 maleate vs placebo.
!
The change from Baseline to Day 1 in GEBT gastric half-emptying time as measured by the 13C Spirulina GEBT 
following single dose administration of TAK-906 maleate vs placebo.
!
The percent change from Baseline to Day 7 in GE time as measured by the SmartPill.
!
Pharmacokinetics: Plasma PK parameters for TAK-906 (Part 1).
Statistical Considerations:
The primary, secondary, and exploratory endpoints will be analyzed in randomized subjects in Part 1 or enrolled 
subjects in Part 2 who received at least 1 dose of study drug. 
For each of the following, change in prolactin, change in GEBT gastric half-emptying time, change in SmartPill GE 
time and change in 
 
 endpoints, a linear model will be fit; the model will include fixed effects of 
stratification factor, regimen (dose level), a random effect of subject, and a covariate of baseline value. Pairwise 
comparisons will be performed within this linear model, with the point estimate and 95% confidence interval (CI) 
derived.
If there is a significant departure from the assumptions underlying the linear model, nonparametric analyses will be 
performed. Pairwise comparisons will be made via Wilcoxon Rank Sum tests along with Hodges-Lehmann estimate 
and 95% CI.
Sample Size Justification: 
Assuming a standard deviation (SD) of 20% for the percent change from Baseline in GEBT gastric half-emptying 
time, a total of approximately 48 subjects (12 per treatment group) is sufficient to achieve around 80% power to detect 
a difference of 25% between TAK-906 doses and placebo in the GEBT by a 2-sample t-test with a 2-sided significance 
level of 0.05. 
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TAK-906
Study No. TAK-906-1002
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CONFIDENTIAL
1.1
Protocol Amendment No. 04 Summary of Changes
Rationale for Amendment 04
This document describes the changes in reference to the protocol incorporating Amendment 
No. 04.
The primary reason for this amendment is to correct and clarify errors and omissions. Minor 
grammatical, editorial, and formatting changes are included for clarification purposes only. For 
specific descriptions of where the changes are located, see Appendix A. 
Changes in Amendment 04:
1. Changed the body mass index criteria for eligibility.


TAK-906
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CONFIDENTIAL
2.0
STUDY SCHEMATIC 
QD=once daily.


TAK-906
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CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Part 1 (Treatment Groups A, B, C, and D)
Day
Screen-
ing 
Day -28 
to Day-3
-
2
-1
Pre-
dose
Day 1
1
2
3
4
5
6
7
8
9
Early
Termina-
tion
Follow-
Up 
Visit (a)
Administrative procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
--------------------------------------Continuous Review---------------------------------------------
Clinical procedures/assessments
Full physical examination (b)
X
X
X
X
X
Height
X
Weight
X
X (c)
X (c)
X
X
Body mass index
X
Semi-recumbent vital signs (heart rate, 
systolic and diastolic blood pressure)
X
X (d)
X (d)
X (d)
X (d)
X
X
Vital signs (respiratory and heart rates, 
oral [floor of the mouth]/tympanic 
temperature)
X
X (e)
X
X
12-lead ECG Standard
X (e)
X (e)
X(f)
X (f)
X
(f)
X (f)
X
X
TAK-906 maleate / placebo 
administration (g)
X
X
X
X
X
X
X
X
X
GEBT (h)
X
X
X
X
SmartPill ingestion (post-test meal)
X
X
Sliding scale insulin administration
X-------------------------------------------------X
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TAK-906
Study No. TAK-906-1002
Page 12 of 82
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CONFIDENTIAL
Part 1 (Treatment Groups A, B, C, and D)
Day
Screen-
ing 
Day -28 
to Day-3
-
2
-1
Pre-
dose
Day 1
1
2
3
4
5
6
7
8
9
Early
Termina-
tion
Follow-
Up 
Visit (a)
AE Monitoring
------------------------------------Continuous Monitoring-------------------------------------------------
Laboratory procedures/assessments
Hematology
X
X (j)
X (j)
X
X
Urinalysis
X
X (j)
X (j)
X
X
Serum chemistry
X
X (j)
X (j)
X
X
Fingerstick glucose (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemoglobin A1c (HbA1c)
X
β-human chorionic gonadotropin 
(hCG)
X
X
X
X
X
Serum follicle stimulating hormone 
(FSH)
X
Urine drug screen (l)
X
Hepatitis screen
X
Human immunodeficiency virus (HIV) 
Screen
X
Blood samples for deoxyribose nucleic 
acid (DNA) pharmacogenomics (PGx)
X
PK evaluations
Plasma samples for TAK-906 PK (m)
X--------------------------------------------------------X
PD evaluations
Serum samples for PD (n)
X
X
X----------X
X--------X
Other
Test meal (p)
X
X
X
X
Standard meals (q)
X
X
X
X
(a) Follow-up visit will occur approximately 14 days after the last dose of trial drug received. For example, if the subject does not continue to Part 2 or prematurely discontinues at any 
time during the study. Subjects who complete Part 1 and continue to Part 2 will not complete a 14-day follow-up, but will follow the 7-day washout procedure.
(b) Predose Day 1 physical examination may be done within approximately 48 hours predose Day 1 and 24 hours post Day 7 am dose.
(c) Weight will be obtained Predose Day 1 and 24 hours postdose Day 7.
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TAK-906
Study No. TAK-906-1002
Page 13 of 82
Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
(d) Vital sign measurements will occur:
–
Predose Day 1 and 90 minutes postdose.
–
Predose Day 4.
–
24 hours post AM dose on Day 7.
(e) Vital signs and 12-Lead ECG will be performed within approximately 1 hour predose on Day 1. The Screening ECG must include 60-second deep inspiration and expiration to 
exclude autonomic neuropathy.
(f) 12-lead ECG on Days 1, 4, and 5 will be obtained at 90 minutes (1.5 hour) post AM Dose. The 12-Lead ECG on Day 8 will be performed 24 hours after the Day 7 AM dose. 
(g) TAK-906 or matching placebo will be administered as a witnessed dose at approximately 0700-0800 and at approximately 1500-1600. On Day 9, only the morning dose will be 
administered.
(h) GEBT in Part 1 will be performed at Screening (unless one was performed within 12 months that showed delay in GE) and Day -1, starting with breath sample collection before 
the test meal (2 samples), after the test meal at 15-minute intervals through 60 minutes post meal, and then at 30 minute intervals until 4 hours post meal. GEBT will be performed on 
Days 1 and 7 with breath sample collection before the test meal (2 samples), after the test meal at 15-minute intervals through 60 minutes post meal, and then at 30 minute intervals 
until 4 hours post meal (5 hours postdose).
(i) 
(j) Predose hematology, chemistry and urinalysis test may be done within approximately 24 hours predose Day 1 and 24 hours following the Day 7 dose.
(k) Diabetes mellitus only: If the subject is confined to the CRU (optional), fingerstick glucose measurements will be obtained up to 3 times per day (pre-AM dose, pre-lunch, 
pre-dinner). At all other times (washout and nonconfinement) the subject will obtain a fingerstick glucose measurement pre-breakfast and at bedtime. Pre-test meal values must be 
below 270 mg/dL. If glucose is above 270 mg/dL prior to the GEBT, a sliding scale insulin administration should be implemented.
(l) A urine drug screen will be obtained at Screening.
(m) Plasma for PK TAK-906 will be obtained:
–
Day 1: Predose, 0.5, 1, 1.5, 2, 4, and 8 hours post morning dose.
–
Day 2-6: just before morning dose. 
–
Day 7: Predose, 0.5, 1, 1.5, 2, 4, 8, 24, and 48 hours post morning dose.
(n) Serum for PD (prolactin concentrations) will be obtained:
–
Screening (local laboratory for inclusion/exclusion ONLY).
–
Day -2.
Day 1: Predose, 1, 1.5, 2, 4, and 8, 24 hours post morning dose.
–
Day 7: Predose, 1, 1.5, 2, 4, 8, 24, and 48 hours post morning dose.
(o) 
(p) For GEBT and SmartPill evaluation. On dosing days, the test meal will be administered 1 hour post the AM dose. The test meal will consist of 100 mg 13C–Splatensis, 27 g 
freeze-dried egg mix, 6 saltine crackers, and 180 mL of water. The caloric content of the meal is 238 kcal, and the meal has a balanced composition of 16.9 g carbohydrates, 14.4 g 
protein, and 11.2 g fat.
(q) Lunch will be administered approximately 5 hours post AM dose. If the subject is confined to the clinical research unit (CRU) (optional), dinner will be provided 2-3 hours post 
PM dose. The meals on Day -1, 1, 4 and 7 will be standard. 
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Part 2
Part 2 (Treatment E [Periods 1 and 2] and Treatment F)
Day
Day 1
Hours
-1
Predose
0
0.5
1
1.5
2
4
8
24
48
Early
Termina-
tion
Follow-
Up 
Visit (a)
Administrative procedures
Prior and concomitant medication review
Clinical procedures/assessments
---------------------------------Continuous Review-------------------------------------------------
Full physical examination (b)
X
X
X
Semi-recumbent vital signs (heart rate, systolic and diastolic blood pressure)
X (c)
X
X
X
Vital signs (respiratory rate, oral [floor of the mouth]/tympanic temperature)
X (c)
X
X
X
12-lead ECG standard
X (c)
X
X
X
TAK-906 maleate or metoclopramide administration (d)
X
Sliding scale insulin as needed (e)
X
AE Monitoring
-----------------------Continuous Monitoring-------------------------------------------------
Laboratory procedures/assessments
Fingerstick glucose (e)
X-----------------------------------------------------------------------------------------------X
hCG 
X
X
X
PK evaluations
Plasma samples for metoclopramide PK (Group F)
X
X
X
X
X
X
X
X
X
Other
High fat breakfast (Group E) (h)
X
Standard meals (i)
X---------------------------------------------X
(a) Follow-up visit will occur approximately 14 days after the last dose of trial drug received in Part 2 or if the prematurely discontinues at any time during the study. Else, a 7-day 
washout separates each dosing period (ie, fed, fasted) in Part 2 food-effect arm (Group E).
(b) Predose Day 1 physical examination may be done within approximately 48 hours predose Day 1.
(c) Vital signs and 12-lead ECG will be performed within approximately 1 hour predose on Day 1. 
(d) Subjects will be given either a single-dose of 25 mg TAK-906 with a high fat breakfast or in the fasted state (Treatment Group E) or 10 mg metoclopramide (1 hour before test 
meal) (Treatment Group F).TAK-906 or metoclopramide will be administered as a witnessed dose at approximately 0700-0800.
(e) Diabetes mellitus only: If the subject is confined to the CRU, fingerstick glucose measurements will be obtained up to 3 times per day (pre-AM dose, pre-lunch, pre-dinner). At all 
other times (washout and nonconfinement) the subject will obtain a fingerstick glucose measurement pre-breakfast and at bedtime. Pre-test meal values must be below 270 mg/dL. If 
glucose is above 270 mg/dL prior to the GEBT, a sliding scale insulin administration should be implemented.
(f) 
 
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(g)
 
(h) Subjects will be given either a single-dose TAK-906 maleate 25 mg between 0700 and 0800 (after at least an 8-hour fast) approximately 30 minutes after the start of a high-fat 
breakfast, or in the fasted state, ie, Period 1 or 2 (Group E). 
(i) If the subject is confined to the CRU, lunch will be administered approximately 5 hours post AM dose, dinner will be provided 2-3 hours post PM dose.
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4.0
INTRODUCTION
4.1
Background
The overall program strategy is to develop TAK-906 for patients with gastroparesis (GP), a 
disorder of the stomach characterized by delayed gastric emptying (GE) in the absence of 
mechanical obstruction. Symptoms are chronic with episodic symptom exacerbation [1]. These 
symptoms may include nausea, vomiting, early satiety, abdominal pain, and postprandial fullness. 
The prevalence of gastroparesis in the United States (US) is 24.2 per 100,000 [2]. In cases of 
chronic gastroparesis, diabetic (29%), postsurgical (13%), and idiopathic (36%) etiologies 
comprise the majority of cases in the tertiary referral setting [3]. Currently in the United States, 
there exists a large unmet medical need because there are no approved therapies for the chronic 
treatment of diabetic gastroparesis. Validated targets for gastroparesis are the D2 and D3 dopamine 
(DA) receptors. The D2 receptor antagonist metoclopramide is indicated for the short-term 
treatment of acute and recurrent diabetic gastroparesis and has been limited in dose and duration of 
treatment by well-documented toxicities, the most notable of which are a category of movement 
disorders known as extrapyramidal symptoms (EPS) [4]. EPS are caused by the blockade of DA 
D2 receptors in the dorsal striatum and thus are potential side effects of all centrally-penetrant 
drugs that share this mechanism of action, particularly selective DA D2 antagonists. Of greatest 
concern is tardive dyskinesia, a severe and often irreversible EPS. The risk of developing tardive 
dyskinesia increases with dose level and duration of treatment and as such, the United States 
package insert includes a black box warning regarding the chronic use of metoclopramide for 
longer than 12 weeks [5].
Domperidone is a peripherally-acting DA D2/D3 receptor antagonist marketed for use as an 
anti-emetic and prokinetic agent in a number of countries worldwide, although not in the United 
States due to its cardiovascular safety profile which includes a risk for drug-induced long QT 
syndrome, torsades de pointes, and sudden cardiac death [6].
DA receptor antagonists are effective in the treatment of delayed GE and GP symptoms because of 
the role of D2 and D3 receptors in the upper gastrointestinal (GI) tract and in the area postrema 
which controls vomiting [7-9]. Both of these areas are outside of the blood brain barrier. 
Therefore, a peripherally-selective D2/D3 antagonist could achieve the desired efficacy without the 
undesired central nervous system (CNS) effects [10,11]. TAK-906 is a peripherally selective
(ie, very limited penetration of the blood brain barrier) DA D2/D3 receptor antagonist. It 
demonstrated suitable pharmacokinetic (PK) and pharmacodynamic (PD) activity in a phase 1 trial 
in healthy volunteers without the CNS liabilities of metoclopramide or cardiac liabilities 
associated with domperidone. Therefore TAK-906 is expected to reduce nausea and vomiting, and 
to have prokinetic effects, without the side effects which restrict the use of other D2/D3 antagonist.
TAK-906 shows rapid absorption. Half-life following a single oral (PO) dose averaged 
approximately 4 hours when administered in the fasted state. Food had a significant impact on 
reducing the exposure to TAK-906.
To date, there are no development and reproductive toxicity data available for TAK-906.


TAK-906
Study No. TAK-906-1002
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Please refer to the TAK-906 Investigator’s Brochure for complete information on the 
investigational product.
In conclusion, TAK-906 maleate is a promising therapeutic for the treatment of gastroparesis. 
4.2
Rationale for the Proposed Trial
There are approximately 13 million patients with GP in United States, European Union, and Japan. 
The most common causes are idiopathic (~36%) and diabetes (~29%). TAK-906 is a D2/D3 DA 
antagonist belonging to a class of prokinetic drugs (eg, domperidone and metoclopramide) shown 
to be effective in the treatment of GP. 
This proof-of-concept trial is designed to evaluate the safety, PK, and PD for TAK-906 in the 
population intended for compound development, ie, subjects with diabetic gastroparesis (DG) or 
idiopathic gastroparesis (IG). For a small proof-of-concept trial, it is prudent to limit the trial 
population to reduce variability, and to focus on the target trial population for phase 3. This trial 
will evaluate the effect of TAK-906 and metoclopramide on GE and the symptoms of GP using the 
instruments proposed for later stage development. In addition, this study will evaluate the effect of 
food on the PK of TAK-906 in the GP population.
4.3
Benefit/Risk Profile
There is no expected clinical benefit to the trial participants.
In vitro, TAK-906 showed no potential for cytochrome P-450 (CYP) enzyme inhibition (2C9, 
2C19, and 3A4) or induction (3A4). To date, no drug-drug interaction data are available for 
hormonal contraceptive use during TAK-906 administration. Additionally, since full reproductive 
toxicity studies have not been completed to date, the combination of caution and the use of highly 
effective double-barrier contraceptives (Appendix E) in a short study provide an adequate safe 
guard against pregnancy during the dosing period. 
Potential risks are based on clinical findings, the mechanism of action, and nonclinical findings. 
Also, there is minimal risk associated with study procedures including scheduled, periodic 
phlebotomy (limited to <500 mL), and noninvasive procedures including vital sign assessments 
and electrocardiograms (ECGs). 
There is a very small risk for the SmartPill to be lodged in the gastrointestinal (GI) tract. While 
most will eventually pass, there is a risk that it may need to be removed surgically. 
For the subjects with diabetes, there is a possibility that the glucose control may be disrupted 
because of the fasting and the study medication. This is transient and can usually be managed 
proactively through closer glucose monitoring. 
The principal mitigation for these risks include appropriate selection of the study populations, the 
clinical research unit (CRU) study setting permitting close monitoring and rapid institution of 
appropriate care as needed, appropriate specified monitoring procedures, and utilization of 
experienced staff trained in study procedures. 
Overall, the risk:benefit profile is considered appropriate for this trial.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypotheses
!
Multiple twice daily (BID) administration of TAK-906 maleate in subjects with GP will be 
safe and well tolerated, based on an assessment of clinical and laboratory adverse events 
(AEs), to permit continued clinical investigation. 
!
Following the first dose, 1 or more well-tolerated doses of TAK-906 maleate will result in a 
3-fold increase in serum prolactin at the maximum observed concentration (Cmax) of serum 
prolactin as compared with Baseline for each period. Moreover, no clinical evidence of 
prolactinemia will be observed following multiple doses in any dose groups. 
!
Following treatment with TAK-906 maleate, a D2/D3 antagonist, at least 1 dose of TAK-906 
maleate is superior to placebo for improving GE as measured by GE time using the gastric 
emptying breath test (GEBT). A difference between TAK-906 and placebo of 25% is expected.
!
Following treatment with TAK-906 maleate, a D2/D3 antagonist, at least 1 dose of TAK-906 
maleate is superior to placebo for improving GE as measured by GE time using the SmartPill. 
A difference between TAK-906 and placebo of 25% is expected.
!
 
 
 
5.2
Trial Objectives
5.2.1
Trial Primary Objective
The primary objective of the study is: 
!
To evaluate the safety and tolerability of TAK-906 in subjects with GP.
5.2.2
Trial Secondary Objectives
The secondary objective(s) of the study are:
!
To assess the prolactin PK/PD relationship in subjects with GP.
!
To demonstrate the effect of TAK-906 on GEBT. 
5.2.3
Trial Exploratory Objectives
Exploratory objectives of this study are: 
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5.3
Endpoints
5.3.1
Primary Safety Endpoint
The primary safety endpoint of the study is key safety and tolerability as assessed through physical 
examinations, vital signs, ECG, and laboratory assessments, as well as collection of serious and 
nonserious AEs.
5.3.2
Secondary Endpoints 
Secondary endpoints include: 
1. The change in serum prolactin from Baseline to Day 1 at time of first occurrence of Cmax (tmax) 
for TAK-906 following administration with TAK-906 maleate vs placebo.
2. The change from Baseline to Day 7 in GEBT gastric half-emptying time as measured by the 
13C Spirulina GEBT following multiple doses of TAK-906 maleate vs placebo.
3. The change from Baseline to Day 1 in GEBT gastric half-emptying time as measured by the 
13C Spirulina GEBT following single dose administration of TAK-906 maleate vs placebo.
4. The percent change from Baseline to Day 7 in GE time as measured by the SmartPill.
5. Pharmacokinetics: Plasma PK parameters for TAK-906 (Part 1).
5.3.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 2a, randomized, double-blind and open-label, placebo and active-comparator 
controlled trial to evaluate the safety, PK, and PD for TAK-906 in subjects with DG or IG. The 
trial will consist of 2 parts and is designed to allow all enrolled subjects to participate in each part 
of the study, at the discretion of the investigator. Subjects may decline participation at any time 
during the study.
Subjects will include men and women aged 18 to 75 years, inclusive, with DG or IG who have
been diagnosed with documented slow GE and a minimum of 3-month history of symptoms 
consistent with GP, including postprandial fullness or nausea, vomiting, abdominal pain, loss of 
appetite, and early satiety.
6.1.1
Part 1
As shown in Table 6.a, approximately 48 subjects will be randomized into 1 of 3 active treatment 
arms or a placebo arm to receive trial drug in a double-dummy manner for 9 consecutive days, for 
a total of 17 doses (ie, BID Days 1 to 8 and morning dose on Day 9). All trial drug dosing will be 
under fasted conditions.
Table 6.a
Doses for Part 1
Treatment Group
N (a)
Trial Drug
A
12
TAK 906 maleate 5 mg BID
B
12
TAK 906 maleate 25 mg BID
C
12
TAK 906 maleate 100 mg BID
D
12
Placebo BID
(a) A minimum of 4 DG and IG in each treatment arm.
GE will be evaluated following a test meal using a GEBT, and GE and motility will also be 
evaluated using SmartPill technology. 
Subjects will be weaned off all medications to treat GP or the symptoms of GP at least 10 days 
prior to assessment of GP on Day -1. A GEBT will be performed during Screening to confirm 
eligibility. If a subject has had a scintigraphy or GEBT within the last 12 months that showed 
delayed in GE, this may be considered and a screening GEBT would not be required. 
A baseline GEBT will be performed on Day -1, and repeated on Days 1 and 7. An 8-hour fast is 
required prior to each GEBT. The GEBT performed on Day -1 will not be used to confirm 
eligibility. A second noninvasive measure of GE and motility will be performed concurrently with 
the GEBT at Baseline (Day -1) in the form of SmartPill motility monitoring, and repeated on 
Day 7. This will serve as a second validated quantitative measure of GE.
Prior to each GEBT and/or SmartPill assessment, subjects will be required to fast the evening 
before the dose (from 2300), and return to the CRU for witnessed doses on each subsequent day of 


TAK-906
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dosing. This procedure will be repeated for the Days 1 (GEBT) and 7 (GEBT and SmartPill) 
procedures.
The first dose of trial medication should be given between approximately 0700 and 0800 (after at 
least an 8-hour fast) and the subject will remain fasted, with the exception of the trial meal at 
1 hour post AM dose, until 4 hours post-test meal (5 hours postdose). After the test meal, breath 
samples will be collected at 15 minute intervals through 60 minutes post meal, with the remaining 
samples collected at 30 minute intervals until 4 hours post meal (5 hours postdose). On Days 2 
through 8, trial medication will be given BID in the morning as a witnessed dose at the CRU 
(approximately 0700 and 0800) an hour prior to breakfast and 8 hours later in the afternoon 
(approximately 1500 and 1600), 2 hours after the last meal and at least an hour before the next 
meal. On Day 9 the trial medication will be given only in the morning. 
An overview of the diet/meal considerations relative to dosing, GEBT, and SmartPill are presented 
in Section 7.4.1.
The dosing period will be for 9 days and total of 17 doses (ie, BID Days 1 to 8 and morning dose on 
Day 9). 
To assess GP symptoms, 
 
 
 
 
 
 
Blood samples for assessment of TAK-906 concentrations in plasma will be collected at scheduled 
time points from predose on Day 1 to 48 hours after Day 7 dose. 
Blood samples for assessment of prolactin concentrations in serum will be collected at Screening 
and scheduled time points from Day -2 to 48 hours after Day 7 dose.
6.1.2
Part 2
An assessment of the food effect on PK of TAK-906, and separately, a comparison of TAK-906 to 
an active comparator (metoclopramide) will be assessed in Part 2, the open-label period of the 
study. All subjects who participated in Part 1 of the study are eligible to participate in all treatment 
groups in Part 2 following a minimum 7-day washout from the last dose in Part 1. Approximately 
18 subjects who completed Part 1 of the study will be enrolled into Part 2 of the study. At the 
discretion of the investigator, approximately 6 subjects will be enrolled in Treatment Group E 
(food effect), and they will receive TAK-906 maleate 25 mg with and without food in a crossover 
design. A minimum 7-day washout will separate the doses in each period. An additional 
12 subjects who complete Part 1 of the study will be enrolled at the discretion of the investigator in 
Treatment Group F (active comparator). In Treatment Group F, a known promotility agent in the 
form of metoclopramide will serve as an active comparator to confirm the responsiveness of the 
GEBT test. All subjects will remain blinded until all subjects have completed Part 1 of the study.
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Blood samples for assessment of TAK-906 or metoclopramide concentrations will be collected at 
scheduled time points from predose on Day 1 to 48 hours postdose.
Table 6.b
Doses for Part 2
Treatment Group
N (a)
Trial Drug
Period 1 (a)
Period 2 (a)
E
~ 6
Single dose TAK-906 maleate 
25 mg 
Fed
Single dose TAK-906 maleate 
25 mg 
Fasted
F (b)
~ 12
Single dose metoclopramide 10 mg
(a) There will be a minimum of 7 days washout between doses in Periods 1 and 2.
(b) A minimum of 4 subjects with DG and 4 subjects IG will be enrolled.
A GEBT will be performed for Day -1 and Day 1 for the metoclopramide group. An 8-hour fast is 
required prior to each GEBT. The GEBT performed on Day -1 will not be used to confirm 
eligibility. 
Subjects may take rescue medication for nausea under the circumstances described in 
Section 8.1.2.
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design 
This study was designed as a randomized, double-blind (Part 1) and open-label (Part 2), placebo 
and active-comparator controlled study in men and women with DG or IG. Since diabetes mellitus 
affects both genders, it is important to include both men and women into the study. In a review of 
the prevalence of gastroparesis in Olmsted County, Minnesota from 1996 to 2006, it was found 
that almost 70% of patients were women. Since GP is a complication of diabetes mellitus, it is 
anticipated that many of these patients would be of child bearing age, and therefore, it is important 
to test early whether these patients are likely to benefit from therapies such as TAK906 [12]. 
Additionally, the recent approval of an instrument (GEBT) that doesn’t require radiation removes 
another potential barrier for the inclusion of women.
For Part 1 of the study, which has 3 TAK-906 maleate arms and 1 placebo arm, a parallel design 
was selected as it was determined more likely facilitate trial recruitment and retention. For Part 2 
food effect, PK is an objective measure of response; thus open-label design is acceptable. For 
Part 2 metoclopramide arm, a known promotility agent in the form of metoclopramide 10 mg and 
known to demonstrate a promotility effect even following a single dose, will serve as an active 
comparator to confirm the responsiveness of the GEBT test.
6.2.2
Rationale for Dose 
Data from the phase 1 single- and multiple-ascending dose (SAD and MAD) trial in healthy 
volunteers were used to select doses for the phase 2a trial. Several considerations were given to 
dose selection: safety, tolerability, PK, and PD (prolactin). Prolactin has been used as a measure of 


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target engagement. The plasma TAK-906-prolactin concentration relationship was characterized 
and was used to estimate prolactin concentrations for several dosing regimens (BID fasted). The 
maximum dose selected (100 mg BID) is predicted to be associated with nearly maximum 
prolactin production at steady state. This dose was also shown to be safe and well tolerated. The 
half maximal effective concentration (EC50) estimate for TAK-906-prolactin concentration 
relationship is estimated to be approximately 5 mg BID; therefore this dose is the lowest dose 
selected.
A dose of TAK-906 maleate 25 mg was selected for testing food effect to allow direct comparison 
with data collected in food-effect portion of the phase 1 SAD study in healthy subjects.
Metoclopramide 10 mg was selected for a comparator as it has a similar mechanism of action to 
TAK-906 and is currently indicated to treat GP in diabetic patients.
6.2.3
Rationale for Endpoints
The PK, PD, and safety measurements in this study are used widely and are recognized as reliable, 
accurate, and relevant.
DA inhibits prolactin production by pituitary lactotroph cells. Thus, when the D2 receptor is 
inhibited, serum prolactin levels rise and can serve as a marker for D2 DA receptor engagement. 
The hallmark of patients with GP is delayed GE, therefore the intended benefit from TAK-906 
therapy is an improvement in GE. There are a number of modalities to objectively measure GE. 
Radiographic scintigraphy is the most established and widely published, but it is associated with 
significant amount of radiation exposure and requires access to centers knowledgeable in the 
techniques to standardize across centers. Two other validated tests to assess GE are GEBT and 
SmartPill motility capsule. The GEBT is a nonradioactive, noninvasive, PO administered test for 
measuring the rate of solid phase GE in adults. The GEBT has been validated against the gold 
standard reference method of gastric scintigraphy. SmartPill is an ingestible capsule that measures 
pressure, pH and temperature as it travels through the GI tract to assess GI motility. SmartPill 
eliminates radiation exposure and is the only motility test that provides a complete transit profile of 
the GI tract. It provides an additional element of data to support the promotility effect of TAK-906.
 
 
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6.2.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, timing of the SmartPill, GEBT, and timing of meals relative to study drug 
administration are critical procedures. Specifically:
!
The SmartPill capsule should be ingested immediately following the completion of the test 
meal at Baseline (Day -1) and Day 7.
!
At any predose and postdose time point, GEBT and timing of meals needs to be collected as 
close to the exact time point as possible.
!
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
!
The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
6.3
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 2a assessment of TAK-906 maleate in humans, and the PK, PD, and safety profiles 
of the compound are still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of phase 2a clinical trials. Modifications to the dose, 
dosing regimen, and/or clinical or laboratory procedures currently outlined below may be required 
to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety monitoring 
of the trial subjects. 
Every effort should be made for all subjects to participate in the SmartPill assessment; however, if 
a subject does not meet the Inclusion/Exclusion criteria for the SmartPill but is otherwise eligible 
to participate in the clinical study, this test may be optional following discussion with the sponsor.
Some alterations from the currently outlined dose and/or dosing regimen may be permitted based 
on newly available data, but the maximum daily dose/exposure detailed in Section 6.2.2, may not 
exceed those currently outlined.
!
The dose may be changed in Part 2.
!
Part 2 may be omitted.
!
Lengthening of the washout Parts 1 and 2.
!
Decrease of the washout period between doses if supported by safety and PK evidence.
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
In the event a subject is unable to swallow the SmartPill they may continue participation in the 
study. 

Additional subjects may be entered into Part 2 of the study up to approximately 12 subjects.

Rescue medications given around ECGs and routine blood draws are permitted.
The PK/PD sampling scheme currently outlined in the protocol may be modified during the trial 
based on newly available PK or PD data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional PD markers.
Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This may include 
repeat samples or modified PK/PD time points based on emerging data. The total blood volume 
withdrawn from any single subject will not exceed the maximum allowable volume during his/her 
participation in the entire trial. 
The timing of planned safety procedures for assessment (eg, vital signs, ECG, safety laboratory 
tests, etc) currently outlined in the protocol may be modified during the trial based on newly 
available safety, tolerability, PK, or PD data (eg, to obtain data closer to the time of peak plasma 
concentrations). These changes will not increase the number of trial procedures for a given subject 
during his/her participation in the entire trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatinine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the Trial File and forwarded to the investigator for retention. The letter must be 
forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.4.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
trial or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.4.3
Definition of Trial Discontinuation
A primary objective of this early phase 2a trial is to identify dose and/or dosing regimen that 
achieves PK, PD, and/or biologic targets in humans based on preclinical or early clinical 
data. Therefore, it is possible that trial subjects may not receive all doses specified in the protocol 


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if this objective is achieved at lower dose levels in this trial. This would not be defined as early 
termination of the trial, but rather an earlier than anticipated achievement of the trial objective(s) 
or trial completion

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a nonsafety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a nonsafety-related reason. 

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons: 

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical or preclinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.4.3.1
Criteria for Premature Termination or Suspension of the Trial or Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practices (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the trial, or as otherwise permitted by the 
contractual agreement.
6.4.3.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site(s)
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the trial 
or the participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must:
1. Understand the study procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all study procedures and restrictions.
3. Has a documented diagnosis of diabetic gastroparesis or idiopathic gastroparesis.
4. Be man or a woman aged 18 to 75 years, inclusive, at the Screening Visit. 
5. Have a body mass index (BMI) ≥18 and ≤40 (kg/m²) at the Screening Visit. 
6. Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months prior to trial drug administration of the initial dose of trial 
drug/invasive procedure.
7. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the Screening Visit and prior to administration of the initial dose 
of trial drug/invasive procedure.
8. Has a QT interval with Fridericia correction method (QTcF) interval <450 mSec (men) 
<475 mSec (women).
9. Has a serum prolactin <2× upper limit of normal (ULN) at Screening.
10. Has an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <1.5×ULN; 
bilirubin ≤1.5×ULN (except Gilbert syndrome).
11. Meet the following birth control requirements:
–
Is a man who is sterile or agrees to use a highly reliable double-barrier method of 
contraception*, including a condom with spermicide, from trial drug administration on the 
first day of the first dose until 31 days after the last dose of trial drug administration. No 
restrictions are required for a vasectomized man provided the subject is at least 1 year 
post–bilateral vasectomy procedure prior to trial drug administration on first day of the first 
dose. A man whose vasectomy procedure was performed less than 1 year prior to trial drug 
administration on the first day of the first dose must follow the same restrictions as a 
nonvasectomized male. Appropriate documentation of surgical procedure should be 
provided.
–
Is a man who agrees to not donate sperm from trial drug administration on the first day of 
the first dose until 31 days after the last dose of trial drug administration.
–
Is a woman of childbearing potential who agrees to use a highly effective double-barrier 
method of contraception* from signing of informed consent throughout the duration of the 
study and until 31 days after the after the last dose. 


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–
Is a woman with no childbearing potential, defined by at least 1 of the following criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in women aged 
>45 years, 6 months of spontaneous amenorrhea in females aged >45 years with serum 
follicle-stimulating hormone (FSH) levels >40 mIU/mL). Appropriate documentation 
of FSH levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
c) Had a tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
*Details of contraception and pregnancy procedures are found in Appendix E.
12. Has symptoms for GP (ie, chronic postprandial fullness, abdominal pain, postprandial nausea, 
vomiting, loss of appetite and/or early satiety) the past 3 months.
13. Has documented slow GE, with delayed GE by GEBT at Screening defined as ≥80th 
percentile. Note: If a subject has had a documented scintigraphy or GEBT within the last 
12 months that confirms the diagnosis of delayed GE, a screening GEBT would not be 
required. 
14. Has nausea subscale (of ANMS-GCSI-DD) symptom score ≥2 at least 3 of 7 days during 
Screening. 
15. Has glycosylated hemoglobin (HbA1c) <10% (for diabetes mellitus only).
Note: Given the biological variability of glycemic parameters, subjects with a value that does 
not meet the above criteria, but is within 0.2% HbA1c of the qualifying range may, at the 
discretion of the investigator, have a repeat determination performed and use as a qualifying 
parameter in lieu of the original value.
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject: 
1. Subjects who have a history of clinically significant endocrine (apart from diabetes mellitus), 
GI (including motility disorder and intestinal obstruction), cardiovascular, hematological, 
hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including 
stroke and chronic seizures) abnormalities or diseases will be excluded from the trial.
2. Has participated in another investigational trial within 4 weeks prior to the pretrial (Screening) 
visit. The 4-week window will be derived from the date of the last trial procedure and/or AE 
related to the trial procedure in the previous trial to the pretrial/Screening Visit of the current 
trial. 
3. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the clinical 
site or of the sponsor.


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4. Has acute severe gastroenteritis and pronounced dehydration in the 48 hours prior to 
Screening, gastric pacemaker, chronic parenteral feeding or persistent severe vomiting.
5. Has a known disturbance of small intestinal absorption, exocrine pancreatic function, liver 
metabolism, and pulmonary function. 
6. Has a history of anorexia nervosa or bulimia. 
7. Has a history of additional risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, 
family history of Long QT Syndrome), evidence of cardiac autonomic neuropathy, eg, lack of 
respiratory rate variation upon deep breathing.
8. Previous history of bezoars (the presence of retained liquid, bile, or small amounts of poorly 
organized food residue is permitted).
9. Difficulty swallowing solid food or pills.
10. Prior surgery involving the luminal GI tract (cholecystectomy, appendectomy, and 
hysterectomy are permitted if performed >3 months prior to SmartPill test).
11. Any abdominal or pelvic surgery within the past 3 months.
12. Known or history of inflammatory bowel disease.
13. Has active diverticulitis, diverticular stricture, and other intestinal strictures.
14. Has active ongoing cancer. In addition, subjects with a history of cancer who have received 
treatment within the last 5 years are not eligible to screen.
15. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
16. Has a hypersensitivity to Spirulina, egg, milk, bread, or jam, or wheat allergens.
17. Has a positive alcohol or drug screen.
18. Lactating or pregnant women as determined by positive human chorionic gonadotropin (hCG) 
test at Screening and within 24 hours of the first dose.
19. Is breastfeeding or has breastfed in approximately the last 6 months.
20. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or human 
immunodeficiency virus (HIV) (confirmatory testing is allowed; most sensitive test should 
take precedence).
21. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
prior to the pretrial Screening Visit. 
22. Is unable and/or unwilling to refrain from or anticipates the use of any medication, including 
prescription and nonprescription drugs or herbal remedies beginning approximately at least 10 
days prior to assessment of GP on Day -1, throughout the trial (including washout intervals 


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between treatment periods), until the posttrial visit. There may be certain medications that are 
permitted. See Section 7.3.
Note: Hormone replacement therapy (HRT) and thyroid dysfunction: HRT are allowed 
(eg, levothyroxine, continuous HRT), but subjects should be on stable regimen for at least 
6 weeks, and are expected to remain on that stable regimen during the treatment period and 
through 14 days after the last dose of trial drug.
23. Chronic daily use of nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, etc).
24. Uses medications that prolong the QT/ corrected QT interval.
25. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass 
is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce] per day).
26. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated 
beverages per day.
27. Has a substance-abuse disorder.
28. Has a consistent fasting glucose of approximately ≥270 mg/dL (14.99 mmol/L) during any 
visit up to and including the randomization visit (Period 1 Day 1 predose). 
Note: If the subject meets this exclusion criterion AND the investigator believes that the value 
is not consistent with the subject’s current self-monitoring blood glucose values, the subject 
should not be excluded at this time. The visit can be repeated within 5 to 7 days.
29. Has had diabetic ketoacidosis (within the prior 4 weeks).
30. Use of cardiac medical devices such as pacemakers and defibrillators (bladder stimulators, 
spinal stimulators, medication infusion devices, insulin pumps, continuous glucose monitors) 
are permitted.
31. Subject is unable or unwilling to comply with the study rules, regulations, and procedures.
7.3
Excluded Medications, Supplements, Dietary Products
7.3.1
Prohibited Medications
7.3.1.1
Medications Which May Alter Gastric pH (for SmartPill) 
1. Proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, dexlansoprazole, 
pantoprazole, rabeprazole) for 7 days prior to study, including the day of SmartPill ingestion.
2. Histamine2 receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine) for 3 days 
prior to study including the day of SmartPill ingestion.
3. Antacids (containing magnesium, aluminium, or calcium carbonate) for 1 day prior to study 
including the day of SmartPill ingestion.


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7.3.1.2
Medications That May Affect Gastrointestinal Motility 
The following medications must be discontinued at least 10 days prior to assessment of GP on 
Day -1, including the day of SmartPill ingestion (if subject develops nausea to the degree that 
study discontinuation is contemplated, he or she may take promethazine, prochlorperazine, or 
ondansetron as rescue antiemetics in doses recommended by the site investigator):
1. Prokinetic agents (metoclopramide, domperidone, erythromycin, azithromycin, bethanechol, 
pyridostigmine).
2. Narcotic analgesics (codeine, hydrocodone, oxycodone, methadone, fentanyl, etc).
3. Anticholinergic agents (dicyclomine, hyoscyamine, scopolamine).
4. Cannabinoids (dronabinol, marijuana).
7.3.1.3
Medications to Treat Nausea
The following medications must be discontinued at least 10 days prior to assessment of GP on 
Day -1, including the day of SmartPill ingestion:
1. Aprepitant, dolasetron, granisetron, ondansetron, palonosetron, and prochlorperazine.
7.3.2
Permitted Medications 
Prescription medications for maintenance of stabilized conditions (eg, hyperlipidemia, thyroid 
disease, chronic anxiety or depression, birth control, etc) are permitted if the condition and the 
dose are stable for 3 months prior to study participation.


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Use of excluded agents (prescription or nonprescription) or dietary products is outline in Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Enrollment 
(Days -28 to Predose [Day 1])
Randomization Post-Enrollment (Day 1) 
to Follow-up
Tobacco- and 
nicotine-containing products
Completely restricted
Completely restricted
Cannabis products
Completely restricted
Completely restricted 
Alcohol
Completely restricted 7 days before 
dosing
Completely restricted 7 days before dosing 
At all other times no more than 3 units/day
Xanthine and/or caffeine
Completely restricted 48 hours before 
dosing
Completely restricted 48 hours before 
dosing 
At all other times no more than 6 units/day
Medications
Completely restricted 7 days before 
dosing
Completely restricted (a)
Food substance

Grapefruit /
grapefruit juice
Completely restricted 7 days before 
dosing
Completely restricted

Fruit
No restriction
No restriction

Fruit juice
No restriction
Dosing will occur without consumption of 
fruit juice. Fruit juice is restricted 4 hours 
after dosing.

Mustard green (b)
Completely restricted 7 days before 
dosing
Completely restricted

Charbroiled meat
Completely restricted 7 days before 
dosing
Completely restricted
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by Takeda on a 
case-by-case basis is allowed. 
(b) Mustard green family includes kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard. 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
An overview of the diet/meal considerations relative to dosing, GEBT, and SmartPill are shown in 
Table 7.b. 
Before each GEBT and/or SmartPill assessment in Part 1, subjects will be required to fast from 
2300 the evening before and return to the CRU for witnessed doses on each subsequent day of 
dosing. This procedure will be repeated for the Day 7 (SmartPill and GEBT) procedures.
The first dose of trial medication should be given between approximately 0700 and 0800 (after at 
least an 8-hour fast) and the subject will remain fasted (with the exception of the test meal at 1 hour 
post AM dose) until 4 hours post trial meal (5 hours postdose). 
After the test meal (1 hour postdose), breath samples will be collected at scheduled intervals until 
4 hours postdose. On Days 2 through 8, trial medication will be given BID in the morning as a 


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witnessed dose at the CRU (approximately 700 and 800 AM), an hour prior to breakfast, and 
8 hours later in the afternoon (approximately 1500 and 1600), 2 hours after the last meal, and at 
least 1 hour before the next meal. On Day 9 the trial medication will be given only in the morning. 


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Table 7.b
Timing of Meals Relative to Dosing and Procedures
Part 1
Day -1
Time
Witnessed Dose
GEBT & SmartPill
Meal 
~7:00-8:00
No dose
~8:00-9:00
Test meal (a)
~9:00-10:00
X
~13:00-14:00
CRU Standard Lunch (b)
~15:00-16:00
No dose
~16:00-17:00
CRU Standard Dinner (b)
Day 1 
Time
Witnessed Dose 
GEBT 
Meal
~7:00-8:00
X
~8:00-9:00
Test meal (a)
~9:00-10:00
X
~13:00-14:00
CRU Standard Lunch (b)
~15:00-16:00
X 
~16:00-17:00
CRU Standard Dinner (b)
Days 2 - 6
Time
Witnessed Dose
Meal
~7:00-8:00
X
~8:00-9:00
Breakfast ad lib (b)
~13:00-14:00
Lunch ad lib (b)
~15:00-16:00
X
~16:00-17:00
Dinner ad lib (b)
Day 7
Time
Witnessed Dose 
GEBT & SmartPill
Meal
~7:00-8:00
X
~8:00-9:00
Test meal (a)
~9:00-10:00
X
~13:00-14:00
CRU Standard Lunch (b)
~15:00-16:00
X 
~16:00-17:00
CRU Standard Dinner (b)
Days 8 and 9
Time
Witnessed Dose
Meal
~7:00-8:00
X
~8:00-9:00
Breakfast ad lib (b)
~13:00-14:00
Lunch ad lib (b)
~15:00-16:00
X (no evening dose on Day 9)
~16:00-17:00
Dinner ad lib (b)
(a) The test meal will consist of 100 mg 13C –Splatensis, 27 g freeze-dried egg mix, 6 saltine crackers, and 180 mL of 
water. The caloric content of the meal is 238 kcal, and the meal has a balanced composition of 16.9 g carbohydrates, 
14.4 g protein, and 11.2 g fat. The nature and size of the meal were selected to ensure stability at room temperature, 
palatability, and calorie content that would be consumed entirely, even by patients with suspected gastroparesis and 
upper abdominal symptoms.
(b) Standardized meal will be provided if the subject is confined to the CRU (optional).


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For the food effect portion in Part 2, the dose of trial medication should be given between 0700 and 
0800 (after at least an 8-hour fast) approximately 30 minutes after the start of a high-fat breakfast. 
For metoclopramide portion in Part 2, an 8-hour fast is required prior to each GEBT performed for 
Day -1 and Day 1 for the metoclopramide group. On Day 1, metoclopramide should be given 
between approximately 0700 and 0800 and the subject will remain fasted until the test meal at 
1 hour post metoclopramide dose and until 4 hours post trial meal (5 hours postdose). After the test 
meal (1 hour postdose), breath samples will be collected at scheduled intervals until 4 hours post 
test meal.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the Screening Visit until the Follow-up visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the AE.
2. Liver Function Test (LFT) Abnormalities
In multidose studies, trial drug should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.8.4), if the following circumstances occur at any time 
during trial drug treatment:
–
ALT or AST >8 ULN, or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
3. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the trial. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 


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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category).
6. Trial termination. The sponsor, IRB, or regulatory agency terminates the trial.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial 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 trial. 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 
Early Termination Visit. 
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The trial site should contact the sponsor for the 
replacement subject’s treatment assignment and allocation number. 


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Drug 
8.1.1
Trial Drugs
In this protocol, the term study medication refers to all or any of the drugs defined below. 
TAK-906 maleate capsules and matching placebo capsules for PO administration will be provided 
to the investigator by the sponsor.
Details regarding the composition and extemporaneous preparation of the active ingredient are 
found in the Pharmacy Manual, Compounding Instructions, and/or similar documents. Clinical 
trial drug will be packaged to support enrollment and replacement subjects as required. When a 
replacement subject is required, the sponsor needs to be contacted before dosing.
8.1.1.1
TAK-906 maleate
TAK-906 capsules, consists of TAK-906 maleate, nominally 5 or 25 mg in TAK-906 maleate per 
capsule, along with microcrystalline cellulose, National Formulary (NF) (PH102), sodium starch 
glycolate, NF and magnesium stearate, NF. All filled into size 3 hard gelatin capsule. All capsules 
have the same appearance.
Dose
5 mg Capsule
25 mg Capsule
Placebo Capsule
Placebo
0
0
4
5 mg
1
0
3
25 mg
0
1
3
100 mg
0
4
0
All doses will be overencapsulated to have a similar appearance to placebo. 
8.1.1.2
Placebo
A matching placebo is identical to the TAK-906 maleate capsule presentations 
(ie, overencapsulation) except for an equal amount of microcrystalline cellulose NF in place of 
TAK-906 maleate.
8.1.1.3
Metoclopramide
Metoclopramide 10 mg will be administered according to product prescribing information [5].
8.1.2
Use of Rescue Medication
Subjects may take rescue medication for nausea under the following circumstance:
During screening, subjects may receive up to 2 doses per day of antinausea medication 
(eg, ondansetron), but only after the subject has reported a nausea subscore ≥2. Similarly, 
antinausea medication may be used from Days 1 through 7 only if the nausea subscore is ≥2. All 
doses of rescue medications will be documented and tabulated. 


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Rescue medications given around ECGs and routine blood draws are permitted.
Metoclopramide will not be allowed to be used as a rescue medication from Day -3. 
8.1.3
Clinical Study Drug Labeling
Clinical trial drug packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.4
Clinical Study Drug Inventory and Storage
Clinical trial drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of trial drug must be recorded by an 
authorized person at the trial site. 
8.1.5
Clinical Study Drug Blinding
Part 1 is the double-blind portion of the trial. The trial drug blind is maintained through a 
randomization schedule held by authorized persons only.
Part 2 is the open label portion of the trial; therefore, the sponsor, investigator, and subject will 
know the treatment administered.
8.1.6
Randomization Code Creation and Storage 
Takeda Development Center Americas, Inc. Analytical Sciences Department or designee will 
generate the randomization schedule. Subject randomization will be stratified by the underlying 
condition, ie, DG versus IG. All randomization information will be stored in a secured area, 
accessible only by authorized personnel.
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure
Part 1:
The investigational drug blind is maintained through a randomization schedule held by authorized 
personnel only.
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All study 
assessments and causality should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor or designee should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding. The sponsor must be 
notified as soon as possible if the investigational drug blind is broken. 
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical trial drug received from 
the sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country sponsor personnel or 


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designee will provide appropriate documentation that must be completed for clinical trial drug 
accountability, return, and destruction. 
8.1.9
Ancillary Supplies
All ancillary supplies will be provided by either the site or Takeda, based upon availability. If 
provided by Takeda, unused ancillary supplies will be accounted for and disposed of as directed by 
Takeda or a Takeda designee.


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9.0
TRIAL PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator. For information regarding procedures that are scheduled concurrently, see 
Section 6.2.4.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Parts 1 and 2:
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures. Each subject will be assigned only 1 screening number. Screening 
numbers must not be re-used for different subjects. Any subject who is screened multiple times 
will be assigned a new screening number for each screening.
Part 1:
All eligible subjects will be randomly allocated and will receive a randomization number. Once a 
randomization number is assigned to a subject, it can never be reassigned to another subject. A 
single subject cannot be assigned more than 1 randomization number.
9.1.1.2
Study Drug Assignment
On Day 1 of Part 1, subjects will be assigned a randomization number. The randomization number 
encodes the subject assignment to 1 of 3 active treatment arms or the placebo arm of the trial, 
according to the randomization schedule generated before the trial by the sponsor’s Statistics 
Department or designee. Each participant will be dispensed blinded trial treatment throughout Part 
1 of the trial.
Among subjects who complete Part 1 and are eligible to participate Part 2, approximately 
6 subjects will be assigned to receive TAK-906 maleate 25 mg with and without food in an 
open-label 2-period crossover design. In addition, up to 12 subjects will be assigned to receive 
single dose metoclopramide 10 mg . 
9.1.2
Inclusion and Exclusion 
Each subject is assessed through randomization, according to the eligibility criteria provided in 
Section 7.0.


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9.1.3
Medical History, Prior and Concomitant Medications, and Demographics
Qualified site personnel are to collect subject significant medical history (past and concurrent) per 
the site’s standard of care and appropriate clinical judgment and subject demographics. 
Qualified site personnel are to review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vitamin supplements, nutraceuticals, and 
oral herbal preparations. 
9.2
Clinical Procedures and Assessments
9.2.1
Physical Examinations
Qualified site personnel will conduct physical examinations.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.2.3
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.2.4
Vital Sign Measurement
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include heart rate, systolic blood pressure, and diastolic 
blood pressure. The same method (eg, same size cuff, manual or automated) must be used for all 
measurements for each individual subject and should be the same for all subjects. 
Subjects will need to rest in a semirecumbent position for at least 5 minutes prior to any other 
trial-related procedure.
9.2.5
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Women may need to remove their bra. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QTcF will be used to calculate QT intervals in this trial.


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At the Screening Visit ECG, a 60-second deep inspiration and expiration must be performed to 
rule out autonomic neuropathy.
Before each treatment period/cohort, a predose ECG will be obtained within approximately 1 hour
before dosing of TAK-906 maleate or metoclopramide. This measurement will be used as the 
Baseline. The principal investigator may consult a trial cardiologist as needed to review any 
significant ECG tracings with abnormalities.
During each treatment period, if a subject demonstrates an increase in QTcF interval ≥40 msec 
compared with a predose baseline measurement, the ECG will be repeated within 5 minutes. The 
average value of the QTcF interval from the 2 ECGs will represent the value at that time point. If 
the average QTcF interval increase from Baseline for any postdose time point is ≥40 msec, the 
subject will continue to be monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours 
or until the QTcF is within 40 msec of the baseline value. If prolongation of the QTcF interval 
≥40 msec persists, a consultation with a trial cardiologist may be appropriate and the sponsor 
should be notified.
If the QTcF interval is ≥500 msec, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be telemetry-monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted on 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, 
QT-interval, QTcF-interval, and the interpretation of the ECG profile by the principal investigator.
9.2.6
Trial Drug Administration
For Part 1 of the trial subjects will be randomized on Day 1 into 1 of 3 active treatment arms 
(TAK-906 maleate 5, 25, or 100 mg BID) or a placebo arm to receive trial drug PO in a 
double-dummy manner for 9 consecutive days. 
For Part 2 of the trial, approximately 6 subjects who complete Part 1 (and following a minimum 
7-day washout from the last dose in Part 1)will be enrolled in Treatment Group E (food effect), and 
they will receive PO TAK-906 maleate 25 mg with and without food in a crossover design. A 
minimum 7-day washout will separate the doses in each period. An additional 12 subjects who 
complete Part 1 will be enrolled into Treatment Group F to receive metoclopramide 10 mg.


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9.2.7
AE Monitoring
AE monitoring begins following signing of informed consent and continues throughout the study. 
A complete description of AE collection and procedures is provided in Section 10.0.
9.2.8
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken following a minimum 8-hour overnight fast on the days stipulated in the 
Schedule of Trial Procedures (Section 3.0). The local laboratory will perform laboratory tests for 
hematology, serum chemistries, urinalysis, in addition to other tests at time of Screening to 
determine eligibility (note: prolactin only at screening for inclusion/exclusion).
9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Bicarbonate
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be fractionated
Protein (total)


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9.2.8.2
Diagnostic Screening
Serum
Serum diagnostic evaluations will include the following tests:
HIV 
Hepatitis Screen (hepatitis A virus antibody, HBsAg, 
hepatitis C virus antibody)
β–human chorionic gonadotropin (females only)
FSH (females only)
Prolactin 
Alcohol Screen
Subjects will undergo an alcohol test (breathalyzer or urine, at the discretion of the investigator).
Urine
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine 
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
9.2.9
Symptom Assessments
9.2.9.1
 
.
9.2.9.2
9.2.9.3
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9.2.9.4
9.3
PK, PD, and Pharmacogenetic Samples
Samples for PK, PD, and or other biomarker analysis will be collected as specified in the Schedule 
of Trial Procedures (Section 3.0). Please refer to the Laboratory Manual for information on the 
collection, processing, and shipment of samples to the Central Laboratory. 
The decision as to which plasma and/or serum samples collected will be assayed for evaluation of 
PK and PD will be determined by the sponsor (eg, samples at lower doses may not be assayed if 
samples at higher doses reveal undetectable drug concentrations). If indicated, these samples may 
also be assayed and/or pooled for assay in an exploratory manner for metabolites and/or additional 
biomarkers.
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-906 PK
Plasma
PK measurements
Mandatory
Plasma sample for 
metoclopramide PK
Plasma
PK measurements
Mandatory
Serum sample for PD
Serum
PD measurements
Mandatory
Blood Sample for DNA PGx
Blood
DNA
PGx measurements
Mandatory
PGx=pharmacogenetic.
9.3.1
PK Measurements 
PK parameters will be derived using noncompartmental analysis methods and will be determined 
from the concentration-time data for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all PK computations involving sampling times for 
plasma PK parameters. 
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For TAK-906, the following PK parameters including, but not limited to, will be calculated as 
appropriate:
!
Day 1: Area under the concentration-time curve during a dosing interval (AUCτ),Cmax, tmax.
!
Day 7: AUCτ, Cmax, tmax, terminal disposition phase half-life (t1/2z), observed concentration at 
the end of a dosing interval (Ctrough).
!
!
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be 
prepared before PK parameter computation.
9.3.1.1
Plasma or Serum for PK Measurements
PK blood samples for plasma TAK-906 concentrations will be collected as specified in Parts 1 and 
2 of the Schedule of Trial Procedures (See Section 3.0). The collected blood samples may be 
archived for additional analysis of potential metabolites.
9.3.2
PD Measurements 
9.3.2.1
Serum Samples for Pharmacodynamics
Serum prolactin levels will be measured as a PD target engagement marker using an in vitro 
diagnostic assay (ADVIA Centaur Prolactin assay).
9.3.2.2
GEBT
The GEBT test procedure should be administered under supervision of a health care professional 
although no specialized facilities or specially licensed personnel are required. 
9.3.2.3
SmartPill Motility 
SmartPill is an ingestible capsule that measures pressure, pH and temperature as it travels through 
the GI tract to assess GE and GI motility and will be administered under supervision of a health 
care professional. 
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9.3.3
PGx 
9.3.3.1
Blood Sample for DNA PGx 
When sampling of whole blood for PGx analysis occurs, every subject must sign an informed 
consent/be consented to participate in the trial. PGx is a component of the trial, participation in 
mandatory. 
PGx is the study of variations of deoxyribonucleic acid (DNA) characteristics as related to drug 
response. There is increasing evidence that an individual’s genetic background may impact the PK 
(absorption, distribution, metabolism, and excretion), PD (pharmacologic effects) and/or the 
clinical outcome (efficacy and/or safety).
PGx research in this trial may be conducted to understand how individual genetic variation in 
subjects impacts their trial drug treatment response. This information may also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-906 and other trial 
drugs, to increase understanding of the disease/condition being studied and other related 
conditions, gain a better understanding of the drug pharmacology and for generating information 
needed for research, development, and regulatory approval of tests to predict response to 
TAK-906. 
Whole blood samples for DNA isolation will be collected from each consented subject in the trial. 
If necessary and feasible, a second aliquot of blood may be taken at a later time point if isolation of 
DNA from the first sample was not successful or possible. 
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.4
Confinement
In Parts 1 and 2 of the study, the subject will be confined for approximately the first 8 hours 
following the first dose of medication to allow for intensive PK sampling and close glucose 
monitoring. At the discretion of the investigator, subjects may be requested to remain longer in the 
CRU.


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10.0
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 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.

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 


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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, 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.
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 eCRF, in order to capture this important safety information consistently in the 


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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

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 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
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 Sections 10.0 and 10.1.1).
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE 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 AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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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 AE (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.
10.2.7 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.


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
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.
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, abnormal LFTs, and other laboratory abnormalities) will 
commence at the time the subject signs the informed consent. Routine collection of AEs will 
continue until 14 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 or lost to follow-up. 
10.2.8.2 Reporting AEs
At each study visit, the investigator 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.


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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. All AEs will be documented in the AE page of the eCRF, 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 trial drug.

Outcome of event.

Seriousness.
10.2.8.3 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.


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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.
10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.8 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9). 
10.2.9 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 trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the trial database, subject evaluability, or appropriateness of the 
planned statistical methods.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
11.1.1.2 PK Set
The PK set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug and 
have at least 1 measurable plasma TAK-906 concentration. All subjects with valid PK parameter 
estimates will be included in the summaries and analyses for that parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in the 
PK analyses; however, data for all subjects will be presented in the data listings.
11.1.1.3 PD Set
The PD set for each PD measurement will consist of all subjects who are enrolled, receive at least 
1 dose of study drug, have a baseline value, and have at least 1 valid postbaseline value for 
assessment of the PD measurement. 
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment and overall for all 
subjects in the safety set. Summary statistics (number of subjects, mean, SD, median, minimum, 
and maximum) will be presented for continuous variables (eg, age, weight, and BMI), and the 
number and percentage of subjects within each category will be presented for categorical variables 
(eg, sex, ethnicity, and race). Individual subject demographic and baseline characteristic data will 
be provided in the data listings.


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11.1.3 PK Analysis
Concentrations of TAK-906 will be summarized by treatment over each scheduled sampling time. 
Individual plasma concentration versus time data will be presented in a data listing. Plasma PK 
parameters of TAK-906 will be summarized by treatment using descriptive statistics. 
A more detailed analysis will be presented in the SAP. Additional analyses will be included, if 
appropriate.
11.1.4 PD Analysis 
For each of the following (ie, change in prolactin, change in GEBT gastric half-emptying time, 
change in SmartPill GE time, 
 endpoints), a linear model will be 
fit; the model will include fixed effects of stratification factor, regimen (dose level), a random 
effect of subject, and a covariate of baseline value. Pairwise comparisons will be performed within 
this linear model, with the point estimate and 95% CI derived.
If there is a significant departure from the assumptions underlying the linear model, 
non-parametric analyses will be performed. Pairwise comparisons will be made via Wilcoxon 
Rank Sum tests along with Hodges-Lehmann estimate and 95% CI.
11.1.5 Safety Analysis
The safety set will be used for all summaries of safety parameters. These summaries will be 
presented by treatment.
11.1.5.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) 
with onset occurring within 30 days after the last dose of trial drug (onset date minus last date of 
dose +1≤30) will be included in the summary tables. TEAEs will be summarized by SOC and PT. 
The following summary tables will be included in the report: summary of TEAEs and drug-related 
AEs, relationship of AEs to trial drug (related vs not related), severity of AEs, and SAEs. Data 
listings will be provided for all AEs including TEAEs, AEs leading to trial drug discontinuation, 
and SAEs.
11.1.5.2 Clinical Laboratory Evaluation
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized by 
treatment. Individual results of laboratory tests from hematology, chemistry, and urinalysis that 
meet Takeda’s markedly abnormal criteria will be summarized. All clinical laboratory data will be 
provided in the data listings.
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11.1.5.3 Vital Signs
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized. 
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be 
summarized. All vital sign data will be provided in the data listings.
11.1.5.4 Other Safety Parameters
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized by treatment. Shift tables for each will be generated to show the investigator’s ECG 
interpretations at each postdose collection by the interpretation at Baseline. Individual results of 
quantitative ECG parameters from the 12-lead safety ECGs that meet Takeda’s markedly 
abnormal criteria will be summarized.
All ECG data will be provided in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analyses will be conducted. 
11.3
Determination of Sample Size
Assuming an SD of 20% for the percent change from Baseline in half-emptying time, a total of 
approximately 48 subjects (12 per treatment group) is sufficient to achieve around 80% power to 
detect a difference of 25% between TAK-906 doses and placebo in the GEBT by a 2-sample t-test 
with a 2-sided significance level of 0.05.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. 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, trial drug, subject medical records, informed consent documentation, and 
review of eCRFs 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 trial 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.
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 Food and Drug Administration [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.


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13.0
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 Conference 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 B. 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 Investigator’s Brochure, 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 trial. 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.


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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.


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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.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. The sponsor must be notified 
of consent withdrawal.
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 eCRF).
13.4
Publication, Disclosure, and Clinical Trial 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 


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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.
13.4.2 Clinical Trial 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 TDC Americas 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 trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial 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 Trial 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.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
SAE and pregnancy reporting
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14.1.2 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 Conference on Harmonisation, E6 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 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix C).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix E of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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14.1.3 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.


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14.1.4 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
 
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUCτ
area under the concentration-time curve during a dosing interval
BID
twice daily
BMI
body mass index
CI
confidence interval
Cmax
maximum observed concentration
CNS
central nervous system
CRU
clinical research unit
Ctrough
observed concentration at the end of a dosing interval
CYP
cytochrome P-450 
DA
dopamine
D2/D3
dopamine receptors
DG
diabetes mellitus gastroparesis
DNA
deoxyribonucleic acid
EC50
half maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form 
EPS
extrapyramidal symptoms
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GE
gastric emptying
GEBT
13C-Spirulina gastric emptying breath test
GI
gastrointestinal
GP
gastroparesis
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus 
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IG
idiopathic gastroparesis
IRB
institutional review board
Company
Confidential
Information
Company Confidential Information


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LFT
liver function tests
MAD
multiple-ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MTV
maximum tolerated volume
NF
National Formulary
PD
pharmacodynamic
PGx
pharmacogenetic
PK
pharmacokinetic
PO
oral administration or orally
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
VTF
volume-to-fullness
WBC
white blood cell
WOCBP
woman of childbearing potential
Company
Confidenti
al
Informatio
n
Company Confidential Information


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15.0
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 MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
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 principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date.
eCRFs 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 eCRFs. The completed eCRFs 
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.
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 eCRFs, 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 


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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) 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.


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16.0
REFERENCES
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Gastroenterological Association technical review on the diagnosis and treatment of 
gastroparesis. Gastroenterology 2004;127(5):1592-622.
2. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L, American College of G. Clinical 
guideline: management of gastroparesis. Am J Gastroenterol 2013;108(1):18-37; quiz 8.
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4. Meltzer HY. Update on typical and atypical antipsychotic drugs. Annu Rev Med 
2013;64:393-406.
5. Metoclopramide hydrochloride tablets. Full Prescribing Information. Parsippany, NJ: Actavis 
Pharma, Inc., Revised June 2015.
6. Michaud V, Turgeon J. Domperidone and sudden cardiac death: How much longer should we 
wait? J Cardiovasc Pharmacol 2013;61(3):215-7.
7. Darmani NA, Zhao W, Ahmad B. The role of D2 and D3 dopamine receptors in the mediation 
of emesis in Cryptotis parva (the least shrew). J Neural Transm (Vienna) 
1999;106(11-12):1045-61.
8. Kashyap P, Micci MA, Pasricha S, Pasricha PJ. The D2/D3 agonist PD128907 
(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin- 9-ol) 
inhibits stimulated pyloric relaxation and spontaneous gastric emptying. Dig Dis Sci 
2009;54(1):57-62.
9. Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev 
Endocrinol Metab 2010;5(5):653-62.
10. Yoshikawa T, Yoshida N, Hosoki K. Involvement of dopamine D3 receptors in the area 
postrema in R(+)-7-OH-DPAT-induced emesis in the ferret. Eur J Pharmacol 
1996;301(1-3):143-9.
11. Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L. The abdominal 
visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J 
Physiol Pharmacol 1990;68(2):325-45.
12. Jung HK, Choung RS, Locke GR, 3rd, Schleck CD, Zinsmeister AR, Szarka LA, et al. The 
incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, 
Minnesota, from 1996 to 2006. Gastroenterology 2009;136(4):1225-33.
Company Confidential Information


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Study No. TAK-906-1002
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14 December 2017
CONFIDENTIAL
17.0
APPENDICES
Appendix A
Detailed Description of Amendments to Text 
The primary section(s) of the protocol affected by the changes in Amendment No. 04 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Changed the body mass index criteria for eligibility.
The primary change occurs in Section 7.1 Inclusion Criteria
Initial 
wording:
Have a body mass index (BMI) ≥18 and ≤35 (kg/m²) at the Screening Visit. 
Amended or 
new wording:
Have a body mass index (BMI) ≥18 and ≤4035 (kg/m²) at the Screening Visit. 
Rationale for Change:
To broaden the BMI range for eligibility.


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Appendix B
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 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-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 
eCRFs, 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 


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CONFIDENTIAL
that the regulatory authority has approved the marketing application. 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.


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Appendix C
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 


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CONFIDENTIAL
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
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 that:
a) 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) 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) 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) The subject’s identity will remain confidential in the event that study results are published.
25. If applicable, woman of childbearing potential (WOCBP) (eg, nonsterilized, premenopausal 
women) who are sexually active must use highly effective double-barrier contraception (as 
defined in the informed consent) from signing the informed consent and throughout the 


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Study No. TAK-906-1002
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CONFIDENTIAL
duration of the study, and for 90 days after the last dose of study drug. Regular pregnancy tests 
will be performed throughout the study for all WOCBP. If a subject is found to be pregnant 
during study, study drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information. 
26. Men must use highly effective double-barrier contraception (as defined in the informed 
consent) from signing the informed consent throughout the duration of the study and for 
5 half-lives PLUS 30 days after the last dose of study drug. If the partner or wife of the subject 
is found to be pregnant during the study, the investigator will offer the subject the choice to 
receive unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
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.


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Study No. TAK-906-1002
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CONFIDENTIAL
Appendix E
Pregnancy and Contraception
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
30 days after last dose of study drug, nonsterilized** male subjects who are sexually active with a 
WOCBP* 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. WOCBP who are partners 
of male subjects must use additional contraception as shown in the list containing highly effective 
contraception below.
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
30 days after last dose of study drug, a WOCBP* who are sexually active with a nonsterilized male 
partner** must use a highly effective method of contraception (from the list below). As there is a 
lack of adequate reproductive toxicity data, female subjects should be instructed to use 2 highly 
effective double-barrier methods of contraception/1 highly effective (from the list below) and 1 
effective method (eg, condom with or without spermicidal cream or jelly).
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A female subject is considered a WOCBP, 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 years of age) 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 men 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 procedures 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). In this study, where medications and devices containing hormones are excluded, the 
only acceptable highly effective methods of contraception are: 

Nonhormonal Methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.


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Study No. TAK-906-1002
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CONFIDENTIAL
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.
–
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 5 half-lives 
PLUS 30 days after last dose.
Note: Hormonal contraception may be susceptible to interaction with the investigative 
compound, comparator, concomitant medications, which may reduce the efficacy of the 
contraception method. Because the drug-drug interaction of TAK-906 with hormonal 
contraceptives has not been evaluated, hormonal methods of contraception are not an 
acceptable contraception method.
2. Effective method of contraception (ie, there may be a higher than 1% failure rate), to be used in 
conjunction with a highly effective method of contraception above, is defined as: 
–
Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicidal jellies or creams PLUS male condom).
3. 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.

Sexual abstinence is NOT an acceptable method of contraception.
4. Subjects will be provided with information on highly effective double-barrier 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.
5. During the course of the study, regular serum/urine hCG pregnancy tests will be performed 
only for WOCBP and all subjects (men and women) will receive continued guidance with 
respect to the avoidance of pregnancy and sperm 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 (ie, condom) in males with partners of childbearing 
potential.


TAK-906
Study No. TAK-906-1002
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14 December 2017
CONFIDENTIAL
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?
6. In addition to a negative serum/urine hCG pregnancy test at Screening, WOCBP must also 
have confirmed menses in the month before first dosing (no delayed menses). Subjects must 
also have a negative serum/urine hCG pregnancy test within 24 hours prior to receiving first 
dose of investigational drug, ie, as close as possible and prior to first dose of investigational 
drug, preferably on the same day.
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 (ie, 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? 
–
Is 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
WOCBP will be included in this study.
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-906) should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study or for 5 half-lives PLUS 30 days after 
the last dose, should also be recorded following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the pregnancy occurs during administration of active study drug, eg, after Day 1 of the study or 
within 5 half-lives PLUS 30 days of the last dose of active study drug, the pregnancy should be 
reported immediately to the contact listed in Section 14.1.1, using a pregnancy notification form.


TAK-906
Study No. TAK-906-1002
Page 82 of 82
Protocol Incorporating Amendment No. 04
14 December 2017
CONFIDENTIAL
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the woman/female 
partner of the male subject was participating in a clinical study at the time she became pregnant 
and provide details of the study drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) 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.


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Personal Protected Data

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A 2-Part, Randomized, Double Blind and Open-Label, Placebo and Active-Comparator 
Controlled Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics for TAK-906 in 
Subjects With Diabetes Mellitus and Gastroparesis or With Idiopathic Gastroparesis
NCT Number: NCT03268941
SAP Approve Date: 15 March 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-906-1002
TAK-906-1002: A 2-Part, Randomized, Double Blind and Open-Label, Placebo and Active-
Comparator Controlled Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics 
for TAK-906 in Subjects With Diabetes Mellitus and Gastroparesis or With Idiopathic 
Gastroparesis
PHASE 2a
Version: Final
Date: 15 March 2018
Prepared by:
Based on:
Protocol Version: Amendment 04
Protocol Date: 14 Dec 2017
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.
Personal Property Data


TAK-906-1002
Page 2 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


TAK-906-1002
Page 3 of 37
Statistical Analysis Plan Final
15 March 2018
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 .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Safety Endpoints ........................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Definition of Study Days, Baseline and Study Visit Windows............................12
7.1.2
Missing Data......................................................................................................13
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
............................................................................16
7.8.2
.....................................................................................18
7.8.3
.................................................18
7.8.4
..................................................................19
7.8.5
.....................................................19
7.8.6
Non-Parametric Analysis ...................................................................................19
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.9.1
Pharmacokinetic Analysis ..................................................................................19
7.9.2
Pharmacodynamic Analysis ...............................................................................21
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7.10
Other Outcomes.......................................................................................................22
7.11
Safety Analysis........................................................................................................22
7.11.1 Adverse Events ..................................................................................................23
7.11.2 Clinical Laboratory Evaluations .........................................................................24
7.11.3 Vital Signs and Weight ......................................................................................24
7.11.4 12-Lead ECGs ...................................................................................................25
7.11.5 Other Observations Related to Safety.................................................................25
7.12
Interim Analysis ......................................................................................................25
7.13
Changes in the Statistical Analysis Plan...................................................................25
8.0
REFERENCES..............................................................................................................26
LIST OF IN-TEXT TABLES
Table 7.a
Symptom Assessment Variables.........................................................................16
Table 7.b
Number of Missing Symptom Items Resulting in a Missing Value for 
Composite/Total/Aggregate Score......................................................................19
LIST OF IN-TEXT FIGURES
Figure 4.a
Trial Schematic....................................................................................................9
LIST OF APPENDICES 
Appendix A
Schedule of Trial Procedures..............................................................................27
Appendix B
Clinical Laboratory Tests and Screening ............................................................32
Appendix C
Criteria for Identification of Markedly Abnormal Laboratory Values .................34
Appendix D
Criteria for Abnormal Values for Serum Prolactin..............................................35
Appendix E
Criteria for Markedly Abnormal Values for Vital Signs......................................36
Appendix F
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........37


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3.0
LIST OF ABBREVIATIONS
%CV
percent coefficient of variation
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUCτ
area under the concentration-time curve during a dosing interval
BID
twice daily
BLQ
below the limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum observed concentration
Ctrough
observed concentration at the end of a dosing interval
CPK
creatine phosphokinase
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
DG
diabetes mellitus and gastroparesis
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
GE
gastric emptying
GEBT
gastric emptying breath test
GGT
!-glutamyl transferase
GI
gastrointestinal
GM
geometric mean
GP
gastroparesis
HIV
human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IG
idiopathic gastroparesis
IVRS
Interactive Voice Response System
LDH
lactate dehydrogenase
LLN
lower limit of normal
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LOCF
last observation carried forward
LS
least squares
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
OC
observed case
PD
pharmacodynamics
PK
pharmacokinetics
PO
oral administration or orally
PRO
patient-reported outcome
PT
preferred term
PTE
pretreatment events
QOL
quality-of-life
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDB
standard database
SOC
system organ class
TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of Cmax
TLGs
tables, listings, and graphs
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the study is: 
∀
To evaluate the safety and tolerability of TAK-906 in subjects with gastroparesis (GP).
4.2
Secondary Objectives
The secondary objectives of the study are:
∀
To assess the prolactin pharmacokinetics (PK)/pharmacodynamics (PD) relationship in
subjects with GP.
∀
To demonstrate the effect of TAK-906 on 13C-Spirulina gastric emptying breath test (GEBT).
4.3
Exploratory Objectives
Exploratory objectives of this study are: 
4.4
Study Design
This is a randomized, double blind and open-label, placebo and active-comparator controlled 
trial to evaluate the safety, PK, and PD for TAK-906 in subjects with diabetes mellitus and 
gastroparesis (DG), or idiopathic gastroparesis (IG). The trial will consist of 2 parts and is 
designed to allow all enrolled subjects to participate in each part of the study, at the discretion of 
the investigator. Subjects may decline participation at any time during the study. 
In Part 1, approximately 48 subjects will be randomized into 1 of 3 active treatment arms (ie, 
orally [PO] TAK-906 maleate 5 mg twice daily [BID], 25 mg BID or 100 mg BID) or a 
matching placebo BID arm in a double-dummy manner and a 1:1:1:1 ratio for 9 consecutive 
days, for a total of 17 doses (ie, BID Days 1 to 8 and morning dose on Day 9). Subject 
randomization will be stratified by the underlying condition, ie, DG versus IG. All trial drug 
dosing will be under fasted conditions. Gastrointestinal (GI) emptying will be evaluated 
following a test meal using a 13C-Spirulina GEBT, and GI emptying and motility will also be 
evaluated using SmartPill technology. Blood samples for assessment of TAK-906 concentrations 
will be collected at scheduled time points from predose on Day 1 to 48 hours after Day 7 dose. 
Blood samples for assessment of prolactin concentrations in serum will be collected at Screening 
and scheduled time points from Day -2 to 48 hours after Day 7 dose. 
 
 
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Approximately 18 subjects who completed Part 1 of the study (and following a minimum 7-day 
washout from the last dose in Part 1) will be enrolled into Part 2, the open-label period of the 
study. At the discretion of the investigator approximately 6 subjects will receive TAK-906 
maleate 25 mg with and without food in an open-label crossover design over 2 periods (ie, fed, 
fasted). Blood samples for assessment of TAK 906 concentrations will be collected from predose 
to 48 hours after each dose of TAK-906 maleate. Furthermore, up to an additional 12 subjects 
who completed Part 1 of the study will be enrolled at the discretion of the investigator to 
participate in the evaluation of TAK-906 vs active comparator metoclopramide to confirm the 
responsiveness of the GEBT test. Subject will be blinded to treatment until all subjects have 
completed Part 1. Blood samples for assessment of TAK 906 or metoclopramide concentrations 
will be collected at scheduled time points from predose on Day 1 to 48 hours postdose. 
Key safety and tolerability will be assessed during Parts 1 and 2 through physical examinations, 
vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory assessments, as well as 
collection of serious and nonserious adverse events (AEs). 
After completion of the trial (or following subject withdrawal), all subjects will return for a 
Follow-up Visit 10 to 14 days after their last dose of study medication.
A schematic of the study design is shown in Figure 4.a. A schedule of assessments is listed in 
Appendix A.
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Figure 4.a
Trial Schematic


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Safety Endpoints
The primary safety endpoint of the study is key safety and tolerability parameters as assessed 
through physical examinations, vital signs, ECG, and laboratory assessments, as well as 
collection of serious and nonserious AEs.
5.2
Secondary Endpoints
Secondary endpoints include: 
1. The change in serum prolactin from Baseline to Day 1 at time of first occurrence of Cmax
(tmax) for TAK-906 following administration with TAK-906 maleate vs placebo.
2. The change from Baseline to Day 7 in GEBT gastric half-emptying time as measured by the 
13C Spirulina GEBT following multiple doses of TAK-906 maleate vs placebo.
3. The change from Baseline to Day 1 in GEBT gastric half-emptying time as measured by the 
13C Spirulina GEBT following single dose administration of TAK-906 maleate vs placebo.
4. The percent change from Baseline to Day 7 in GE time as measured by the SmartPill.
5. Pharmacokinetics: Plasma PK parameters for TAK-906 (Part 1).
5.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
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6.0
DETERMINATION OF SAMPLE SIZE
Assuming a standard deviation (SD) of 20% for the percent change from Baseline in GEBT 
gastric half-emptying time, a total of approximately 48 subjects (12 per treatment group) is 
sufficient to achieve around 80% power to detect a difference of 25% between TAK-906 doses 
and placebo in the GEBT by a 2-sample t-test with a 2-sided significance level of 0.05.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Study data will be analyzed and presented separately for Part 1, Part 2 group E (Food Effect) and 
Part 2 group F (metoclopramide) unless otherwise indicated. In general, Part 1 data will be 
analyzed by treatment, Part 2 group E data will be analyzed by regimen (fed vs fasted), and Part 
2 group F data will be analyzed overall. 
Categorical data will be summarized as the number and percentage of subjects in each category.
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. The coefficient of 
variation (%CV) and geometric mean will be included in the summary of continuous data where 
indicated.
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data, and SDs will be presented to 2 more decimal places than the recorded data, 
where appropriate. Where applicable, confidence intervals about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate and p-values will 
be rounded to 3 decimal places prior to assessment of statistical significance.
All statistical tests and confidence intervals (CIs) will be 2-tailed at α=0.05 level for significance
unless otherwise stated.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
All statistical analyses will be performed using the SAS System Version 9.4.
7.1.1
Definition of Study Days, Baseline and Study Visit Windows
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) study drug administration page. Other study days are defined relative to 
Study Day 1, with Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. 
Study days prior to the first dose of study drug will be calculated as: [date of assessment/event –
date of first dose of study drug]. Study days on or after the first dose of study drug will be 
calculated as: [date of assessment/event – date of first dose of study drug + 1]. For Part 2 group 
E, period day will be calculated relative to the date of first dose for that treatment period.
Unless specified otherwise, for all PD, symptom assessment, and safety endpoints from Part 1, 
Baseline is defined as the last non-missing measurement prior to the first dose of study drug.
For PD and safety endpoints from Part 2 group F, Baseline is defined as the last non-missing 
measurement prior to the first dose of study drug in Part 2.
For safety endpoints from Part 2 group E, Baseline is defined as the last non-missing
measurement prior to first dose of study drug for the respective treatment period in Part 2.


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In Part 1, for GEBT and SmartPill, a ±1 study day window is defined for Day 7 visit.
 
 
 
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used in the summary and analysis. In the 
event of 2 observations equidistant to the scheduled visit day, the later of the observations will be 
used.
7.1.2
Missing Data
There will be no imputation of incomplete or missing data unless otherwise indicated. 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in
the summarizing concentration values and deriving of PK parameters. These values will be
flagged in the data listings.
7.2
Analysis Sets
∀
Safety Set: The safety set will consist of all subjects who are randomized (Part 1) or enrolled
(Part 2) and receive at least 1 dose of study drug in the respective part. Subjects in this 
analysis set will be used for demographic, baseline characteristics, and safety summaries.
∀
PK Set: The PK set will consist of all subjects who are randomized (Part 1) or enrolled
(Part 2) and receive at least 1 dose of study drug and have at least 1 measurable plasma 
TAK-906 or metoclopramide concentration. All subjects with valid PK parameter estimates 
will be included in the summaries and analyses for that parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included 
in the PK analyses; however, data for all subjects will be presented in the data listings.
∀
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomized (Part 1) 
or enrolled (Part 2), receive at least 1 dose of study drug, have a baseline value, and have at 
least 1 valid postbaseline value for assessment of at least one of the PD measurement.
∀
Per-Protocol Set (PPS): The PPS will include all FAS subjects who had no major protocol 
violations. The major protocol violation criteria will be defined as part of the blinded data 
review prior to the unblinding of subject's treatment assignment. The categories of major 
protocol violations include: 
a) not meeting inclusion/exclusion criteria defined in the Protocol Amendment 04 [1], 
b) receiving an incorrect study medication that leads to a treatment change,
c) other major protocol violations that may be identified during blinded data reviews.
For Part 1, analyses using the Safety Set and PK Set will be based on the actual treatment the 
subject received. Analyses using the FAS will be based on the randomized treatment the subject 
was assigned. 
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7.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version, will be tabulated.
A summary of screening failures and data listing of inclusion/exclusion criteria responses for 
subjects with violations will be provided. Eligibility for randomization into treatment phase 
(Part 1) will be summarized along with the primary reasons of screen failure as recorded in 
eCRF.
The number and percentage of subjects randomized/enrolled will be summarized by site, and by
treatment group (Part 1) or by enrollment group (Part 2). The number and percentage of subjects 
who comprised each analysis set will also be summarized.
Disposition of all randomized/enrolled subjects will be tabulated. Categories will include:
∀
Subjects who were randomized but not treated (Part 1 only).
∀
Subjects who completed study drug.
∀
Subjects who prematurely discontinued study drug.
∀
Primary reasons for discontinuation of study drug, as entered on the eCRF.
∀
Subjects who completed all study visits.
∀
Subjects who prematurely discontinued study visits.
∀
Primary reasons for discontinuation of study visits, as entered on the eCRF.
Subjects with significant protocol deviations will be summarized and listed as captured on the 
eCRF. For subjects enrolled in both parts, any significant protocol deviations with start date prior 
to Day -1 of Part 2 will be summarized in Part 1.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics, including age at informed consent, gender, ethnicity, 
race, height (cm), weight (kg), body mass index (kg/m2), and underlying disease condition (DG 
vs IG), will be summarized by treatment (Part 1 only) and overall for all subjects in the safety 
set. 
For Part 1, baseline values of PD measurements and symptom assessments (Serum Prolactin, 
GEBT, SmartPill, 
) will also 
be summarized by treatment group and overall based on FAS and will be compared across 
treatment groups using an analysis of variance (ANOVA) model with treatment, and underlying 
disease condition as factors.
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Individual subject demographic and baseline characteristic data will be provided in the data 
listings. Subjects enrolled in both parts of the study will be indicated.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant ongoing
conditions or diseases that are present at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the latest version of 
MedDRA available, and will be summarized by treatment and overall using System Organ Class 
(SOC) and MedDRA preferred term (PT). Summary table will be provided for Part 1 only. The 
table will include number and percentages of subjects, and will be sorted in alphabetical order by 
SOC. Within an SOC, PTs are sorted in decreasing frequency based on the total number of 
subjects. A subject will only be counted once within a particular class even if he/she has multiple 
conditions/symptoms. Summaries will be based on the safety set. There will be no inferential 
analysis of medical history and concurrent medical conditions.
All medical history and concurrent medical condition data will be presented in data listings.
Subjects enrolled in both parts of the study will be indicated.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication stopped at or within 30 days prior to 
signing of informed consent. Medications used from signing of informed consent through the end 
of study will be considered as concomitant medications.
Medication history and concomitant medications will be coded using the latest version of the 
WHO Drug Dictionary available, and summarized by giving the number and percentage of 
subjects by preferred term within each therapeutic class, with therapeutic class sorted in 
alphabetical order and preferred term sorted in decreasing frequency based on the total number 
of subjects. If a subject reports taking 2 drugs belonging to the same class, he/she will only be 
counted once within that class. Summaries of medication history and concomitant medication 
will be based on the safety set. There will be no inferential analysis of medication history and 
concomitant medications.
All medication history and concomitant medications data will be presented in data listing.
Subjects enrolled in both parts of the study will be indicated.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all 
subjects. Summaries and listings of TAK-906 and metoclopramide PK data will be provided. No 
summary statistics for the extent of exposure to study drug or compliance calculations will be 
performed for this study.


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7.8
Efficacy Analysis
Efficacy is evaluated through symptom assessments in Part 1 but is not the primary objective of 
this study. The exploratory analyses and summaries for efficacy will be based on the FAS.
The symptom assessment variables for this study are presented in Table 7.a.
Table 7.a
Symptom Assessment Variables
7.8.1
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7.8.2
7.8.3
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7.8.4
7.8.5
7.8.6
Non-Parametric Analysis
If there is a significant departure from the assumptions underlying the linear model, non-
parametric analyses will be performed instead of ANCOVA. Pairwise comparisons will be made 
via Wilcoxon Rank Sum tests stratified by IG and DG along with Hodges-Lehmann estimate 
and 95% CI.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The schedule of blood samples for PK analysis of TAK-906 and metoclopramide is specified in 
Appendix A.
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The plasma concentration of TAK-906 and any measured metabolites will be summarized by 
treatment group (Part 1) or by regimen (Part 2 group E) over each scheduled sampling time point 
using descriptive statistics (N, arithmetic mean, SD, SE, %CV, median, minimum and 
maximum). For Part 1, the plasma concentration of TAK-906 will be summarized in overall 
population and by underlying disease condition (DG and IG). For Part 2 group F, plasma 
concentration of metoclopramide will be summarized over each scheduled sampling time point 
using descriptive statistics. Individual plasma concentration data versus time will be presented 
together with the descriptive statistics as well as in separate data listing.
The figures for mean plasma concentrations of TAK-906 (both Part 1 and Part 2 group E) and 
metoclopramide (Part 2 group F) versus time (linear and semi-log scale) will be generated. For 
Part 1, mean concentration-time curves will be generated separately for Day 1, Day 7, and Day 1 
- Day 9. The mean concentration versus time curves in Part 1 and Part 2 group F will be 
presented in overall population and by underlying disease condition (DG and IG). 
The figures for individual plasma concentrations of TAK-906 (both Part 1 [Day 1- Day 9] and 
Part 2 group E) and metoclopramide (Part 2 group F) versus time (semi-log scale) will be 
generated.
Plasma PK parameters will be calculated from the concentration-time data for TAK-906, any 
measured metabolites of TAK-906, and metoclopramide using non-compartmental analysis. The 
key PK parameters are listed below:
Part 1- TAK-906
∀
AUCτ: Area under the concentration-time curve during a dosing interval (Day 1 and 7).
∀
Cmax: Maximum observed concentration (Day 1 and 7).
∀
Ctrough: Observed concentration at the end of a dosing interval (Day 2- Day 9).
∀
tmax: Time of first occurrence of Cmax (Day 1 and 7).
Plasma PK parameters of TAK-906, any measured metabolites of TAK-906, and 
metoclopramide will be summarized using descriptive statistics (N, arithmetic mean, SD, SE, 
%CV, median, minimum and maximum). In addition, geometric mean and geometric mean %CV 
will be computed. Individual plasma PK parameters will be presented in data listings. For Part 1, 
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the PK parameters of TAK-906 will be summarized by treatment and day, in overall population 
and by underlying disease condition (DG and IG).
For Part 1, individual plots for AUCτ and Cmax will be generated by treatment (dose) and day, in 
overall population and by underlying disease condition (DG and IG). For Part 2 group E, scatter 
plots for AUC∞and Cmax will be generated by regimen. For Part 2 group F, scatter plots for AUC
∞and Cmax will be generated overall and by underlying disease condition, if applicable.
There will be no inferential analysis of PK parameters.
7.9.2
Pharmacodynamic Analysis
The analyses and summaries for PD will be based on the FAS.
7.9.2.1
Analysis of Serum Prolactin
Summary and analysis of serum prolactin will be performed in Part 1 only. Serum prolactin 
concentrations will be listed. Baseline, postbaseline and ratio of postbaseline relative to baseline
in serum prolactin concentrations will be summarized at each scheduled time point by treatment
group, in overall population and by underlying disease condition (DG and IG). Figures for mean 
serum prolactin concentrations (linear and semi-log scale) and ratio of postbaseline serum 
prolactin concentration relative to baseline versus time will be generated, in overall population 
and by underlying disease condition (DG and IG).
Baseline is defined as the predose concentration on Day 1 and Day 7.
PD parameters, including AUC (using exact method) and Cmax, for Day 1 and Day 7 will be 
derived. PD parameters will be summarized by treatment and day, in overall population and by 
underlying disease condition (DG and IG). The change in serum prolactin from Baseline to 
Day 1 at time of first occurrence of Cmax(tmax) will be quantified by a ratio of Cmaxrelative to 
baseline concentration, and will be assessed using pairwise comparison from an ANCOVA 
model, in overall population and by underlying disease condition (DG and IG) if applicable. The 
model will include treatment and underlying disease condition (for analysis in overall 
population) as fixed factors, natural logarithm of baseline as covariate, and natural logarithm of
ratio between Cmaxand baseline as the response. The appropriate estimates for the differences 
and the associated CIs will be exponentiated to evaluate the ratios under the original scale. 
Geometric mean and geometric mean %CV will be included in the summary of PD parameters. 
AUC will be analyzed in a similar manner with natural logarithm of the AUC as the response. A 
sensitivity analysis based on the PPS will be performed on PD parameters.
7.9.2.2
Analysis of GEBT
For both Part 1 
, baseline and postbaseline GEBT gastric half-emptying time
will be summarized and listed. 
In addition, Change from Baseline and Percent Change from Baseline in GEBT gastric half-
emptying time at Day 1 and Day 7 in Part 1 will be analyzed using ANCOVA models, with 
treatment and underlying disease condition (for analysis in overall population) as fixed factors, 
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and baseline as covariate, in overall population and by underlying disease condition (DG and IG)
if applicable. In case there is a significant departure from the assumptions underlying the linear 
model, non-parametric analysis method described in Section 7.8.6 will be applied. 
For Part 1, figure of mean change from baseline in GEBT gastric half-emptying time over time 
(study day) will be generated by treatment.
Another GEBT metric, the percent dose excreted at time t multiplied by 1000 (kPCD) [4], will be 
summarized at each scheduled time point by treatment group for both Part 1 
.
For Part 1, figure of mean change from baseline in kPCD over time (minutes) will be generated 
by treatment for both Day 1 and Day 7.
Change from day 1 to day 7 in gastric half-emptying time and kPCD will be summarized.
Primary analysis of GEBT parameters will be based on FAS and will exclude subjects who is 
non-compliant to the test meal or test procedure, which is defined as consuming < 90% of the 
test meal (for both gastric half-emptying time and kPCD) or having any incomplete breath 
sample post 30 minutes and not equals 60 minutes (for gastric half-emptying time). 
Two sensitivity analyses will be performed on GEBT parameters:
1. Analysis based on the PPS excluding subjects who is non-compliant to the test meal or 
test procedure as described in the primary analysis.
2. Analysis including all subjects in the FAS regardless whether they are fully compliant to 
the test meal/procedure, unless the parameters are not evaluable.
7.9.2.3
Analysis of SmartPill Motility 
SmartPill will be administered in Part 1 only to assess GE and GI motility. Baseline and 
postbaseline GE time (Gastric Transit Time), Small Bowel Transit Time, and Colonic Transit 
Time measured by SmartPill will be summarized and listed. Percent Change from Baseline to 
Day 7 of these parameters will be analyzed in a manner similar to GEBT, in overall population 
and by underlying disease condition (DG and IG) if applicable. A sensitivity analysis based on 
the PPS will be performed.
In addition, exposure-response relationships may be investigated. A separate analysis plan will 
be prepared prior to the analysis, should it be necessary.
7.10
Other Outcomes
Meal data will be presented in data listing.
7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign 
parameters, 12-lead electrocardiogram (ECG) results.
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All summaries of safety data are based on subjects in the Safety Set. For Part 1, safety data of the 
three TAK-906 dose groups will be summarized separately and pooled (excluding subject 
mapping tables). 
7.11.1 Adverse Events
All AE verbatim terms will be coded by SOC and PT using the latest version of MedDRA 
dictionary.
A treatment-emergent adverse event (TEAE) will be defined as an AE or serious adverse event 
(SAE) that started or worsened after first study drug administration and within 30 days of last 
dose of study drug (onset date – date of last dose + 1 ≤30). For subjects enrolled in both parts, 
any TEAEs with onset date prior to the date of first dose in Part 2 will be summarized in Part 1. 
AEs with missing onset dates will be summarized with TEAEs regardless of severity and 
relationship to study medication.
TEAEs will be summarized by giving the number and percentage (N [%]) of subjects reporting 
any event for each term. The following is a list of TEAE summary tables to be generated. 

Overview of TEAEs (at both subject and event level).

TEAEs by SOC and PT (at both subject and event level).

Subject Mappings for TEAEs.

TEAEs by SOC and PT by underlying disease condition (DG and IG).

TEAEs by PT.

Relationship of TEAEs to Study Drug by SOC and PT. 

Drug-Related TEAEs by SOC and PT.

Intensity of TEAEs by SOC and PT.

TEAEs leading to study discontinuation by SOC and PT (Part 1 only).

Treatment-emergent SAEs by SOC and PT (Part 1 only).

Most Frequent (>=5%) Non-serious TEAEs by SOC and PT (at both subject and event level, 
Part 1 only).
SOCs will be sorted by alphabetical order. Within a SOC, PTs will be sorted in descending order 
based on the total number of subjects with AEs. For each category and overall, subjects reporting 
more than 1 occurrence for a term (SOC or PT) being summarized will be counted only once 
using the most extreme incident (most severe for the intensity tables and related for the 
relationship to study drug tables).
Data listings will be provided for all TEAEs, TEAEs that led to study drug discontinuation, 
TEAEs that led to abnormal liver functions, SAEs, AEs that resulted in death, pretreatment 
events (PTEs), and AEs occurring more than 30 days after the last dose of study medication.


TAK-906-1002
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CONFIDENTIAL
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include chemistry, hematology, urinalysis, and diagnostic 
screening. Refer to Appendix A for scheduled clinical laboratory test measurements and to 
Appendix B for the list of all clinical laboratory tests.
For Part 1, descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical 
safety laboratory variables will be summarized for baseline, postbaseline values, and change 
from baseline by treatment group and overall at each visit. Only the scheduled measurements 
will be included in the summary. No inferential analysis will be performed.
Individual results for hematology and chemistry laboratory tests in Part 1 will be evaluated 
against the Takeda predefined laboratory markedly abnormal value (MAV) criteria (Appendix 
C). All subjects that meet the MAV criteria will be presented in a data listing. If a subject has a 
MAV for a particular laboratory test, all visits for that subject and for that parameter will be 
listed. The number and percentage of subjects with at least 1 postbaseline markedly abnormal 
laboratory test result will be presented by treatment group and overall. All postbaseline clinical 
lab results within 7 days of the last dose, including scheduled and unscheduled measurements 
will be included in the MAV summaries. The mapping of the subjects with postbaseline results 
which meet the MAV criteria will be listed as a table.
All clinical laboratory data will be presented in both SI in the data listings. Laboratory data 
outside of the normal reference range will be flagged on the listing.
In addition, shift in serum prolactin from baseline to postbaseline will be summarized using the
criteria defined in Appendix D. 
7.11.3 Vital Signs and Weight
Vital sign measurements include body temperature, heart rate, respiratory rate, and blood 
pressure. Refer to Appendix A for scheduled vital signs and weight measurement visits.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of vital signs parameters 
and weight will be summarized for baseline, postbaseline, and change from baseline at each 
scheduled time point. Only the vital signs and weight collected at the scheduled visits or time 
points will be included in the summary. No inferential analysis will be performed.
All individual vital signs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix E) will be listed. If a subject has a MAV for a particular vital sign parameter, all visits 
for that subject and for that parameter will be listed. The number and percentage of subjects with 
at least 1 postbaseline markedly abnormal vital sign measurement will be summarized. All 
postbaseline vital signs within 7 days of the last dose, including both scheduled and unscheduled 
measurements, will be included in the MAV summaries. The mapping of the subjects with 
postbaseline results which meet the MAV criteria will be listed as a table.
All vital sign data will be presented in the listings. Vital sign MAVs will be flagged in the 
listings.


TAK-906-1002
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CONFIDENTIAL
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix A. The ECG 
parameters include heart rate, PR interval, QRS duration, QT interval, and QT interval with 
Fredericia’s corrections (QTcF).
Descriptive statistics (N, mean, median, SD, minimum and maximum) of quantitative ECG data 
will be summarized for baseline, postbaseline, and change from baseline at each scheduled time 
point. Only the ECGs collected at the scheduled visits or time points will be included in the 
summary. No inferential analysis will be performed for the observed ECGs.
For ECG interpretation data, shift tables will be provided as the number of subjects to assess 
interpretation status change from baseline to each scheduled postbaseline measurement.
All individual ECGs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix F) will be listed. If a subject has a MAV for a particular ECG parameter, all visits for 
that subject and for that parameter will be listed. The number and percentage of subjects with at 
least one markedly abnormal ECG measurement will be summarized. All post dose ECGs within 
7 days of the last dose, including both scheduled and unscheduled measurements, will be 
included in the MAV summaries. The mapping of the subjects who meet the MAV criteria will 
be listed as a table.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Reproductive System Findings and Pregnancy Test data of female subjects will be presented in 
data listings. Fingerstick Glucose data of subjects with diabetes mellitus will also be listed. 
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
None.


TAK-906-1002
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Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
8.0
REFERENCES
1. TAK-906-1002: A 2-Part, Randomized, Double-Blind and Open-Label, Placebo and Active-
Comparator Controlled Trial to Evaluate the Safety, Pharmacokinetics and
Pharmacodynamics for TAK-906 in Subjects With Diabetes Mellitus and Gastroparesis or 
With Idiopathic Gastroparesis, Millennium Pharmaceuticals, Inc. (Takeda Global Research 
and Development –United States), Protocol No. TAK-906-1002, dated 14 December, 2017.
 
 
 
 
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TAK-906-1002
Page 27 of 37
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15 March 2018
CONFIDENTIAL
Appendix A
Schedule of Trial Procedures
Part 1 (Treatment Groups A, B, C, and D)
Day
Screen-
ing 
Day -28 
to Day-3
-
2
-1
Pre-
dose
Day 1
1
2
3
4
5
6
7
8
9
Early
Termina-
tion
Follow-
Up 
Visit (a)
Administrative procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
--------------------------------------Continuous Review---------------------------------------------
Clinical procedures/assessments
Full physical examination (b)
X
X
X
X
X
Height
X
Weight
X
X (c)
X (c)
X
X
Body mass index
X
Semi-recumbent vital signs (heart 
rate, systolic and diastolic blood 
pressure)
X
X (d)
X (d)
X (d)
X (d)
X
X
Vital signs (respiratory and heart 
rates, oral [floor of the 
mouth]/tympanic temperature)
X
X (e)
X
X
12-lead ECG Standard
X (e)
X (e)
X(f)
X (f)
X
(f)
X (f)
X
X
TAK-906 maleate / placebo 
administration (g)
X
X
X
X
X
X
X
X
X
GEBT (h)
X
X
X
X
SmartPill ingestion (post-test meal)
X
X
Sliding scale insulin administration
X-------------------------------------------------X
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CONFIDENTIAL
Part 1 (Treatment Groups A, B, C, and D)
Day
Screen-
ing 
Day -28 
to Day-3
-
2
-1
Pre-
dose
Day 1
1
2
3
4
5
6
7
8
9
Early
Termina-
tion
Follow-
Up 
Visit (a)
AE Monitoring
------------------------------------Continuous Monitoring-------------------------------------------------
Laboratory procedures/assessments
Hematology
X
X (j)
X (j)
X
X
Urinalysis
X
X (j)
X (j)
X
X
Serum chemistry
X
X (j)
X (j)
X
X
Fingerstick glucose (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemoglobin A1c (HbA1c)
X
β-human chorionic gonadotropin 
(hCG)
X
X
X
X
X
Serum follicle stimulating hormone 
(FSH)
X
Urine drug screen (l)
X
Hepatitis screen
X
Human immunodeficiency virus 
(HIV) Screen
X
Blood samples for deoxyribose 
nucleic acid (DNA) 
pharmacogenomics (PGx)
X
PK evaluations
Plasma samples for TAK-906 PK (m)
X--------------------------------------------------------X
PD evaluations
Serum samples for PD (n)
X
X
X----------X
X--------X
Other
Test meal (p)
X
X
X
X
Standard meals (q)
X
X
X
X
(a) Follow-up visit will occur approximately 14 days after the last dose of trial drug received. For example, if the subject does not continue to Part 2 or prematurely discontinues at 
any time during the study. Subjects who complete Part 1 and continue to Part 2 will not complete a 14-day follow-up, but will follow the 7-day washout procedure.
(b) Predose Day 1 physical examination may be done within approximately 48 hours predose Day 1 and 24 hours post Day 7 am dose.
(c) Weight will be obtained Predose Day 1 and 24 hours postdose Day 7.
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Statistical Analysis Plan Final
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CONFIDENTIAL
(d) Vital sign measurements will occur:
–
Predose Day 1 and 90 minutes postdose.
–
Predose Day 4.
–
24 hours post AM dose on Day 7.
(e) Vital signs and 12-Lead ECG will be performed within approximately 1 hour predose on Day 1. The Screening ECG must include 60-second deep inspiration and expiration to 
exclude autonomic neuropathy.
(f) 12-lead ECG on Days 1, 4, and 5 will be obtained at 90 minutes (1.5 hour) post AM Dose. The 12-Lead ECG on Day 8 will be performed 24 hours after the Day 7 AM dose. 
(g) TAK-906 or matching placebo will be administered as a witnessed dose at approximately 0700-0800 and at approximately 1500-1600. On Day 9, only the morning dose will be 
administered.
(h) GEBT in Part 1 will be performed at Screening (unless one was performed within 12 months that showed delay in GE) and Day -1, starting with breath sample collection 
before the test meal (2 samples), after the test meal at 15-minute intervals through 60 minutes post meal, and then at 30 minute intervals until 4 hours post meal. GEBT will be 
performed on Days 1 and 7 with breath sample collection before the test meal (2 samples), after the test meal at 15-minute intervals through 60 minutes post meal, and then at 30 
minute intervals until 4 hours post meal (5 hours postdose).
(i) 
.
(j) Predose hematology, chemistry and urinalysis test may be done within approximately 24 hours predose Day 1 and 24 hours following the Day 7 dose.
(k) Diabetes mellitus only: If the subject is confined to the CRU (optional), fingerstick glucose measurements will be obtained up to 3 times per day (pre-AM dose, pre-lunch, pre-
dinner). At all other times (washout and nonconfinement) the subject will obtain a fingerstick glucose measurement pre-breakfast and at bedtime. Pre-test meal values must be 
below 270 mg/dL. If glucose is above 270 mg/dL prior to the GEBT, a sliding scale insulin administration should be implemented.
(l) A urine drug screen will be obtained at Screening.
(m) Plasma for PK TAK-906 will be obtained:
–
Day 1: Predose, 0.5, 1, 1.5, 2, 4, and 8 hours post morning dose.
–
Day 2-6: just before morning dose. 
–
Day 7: Predose, 0.5, 1, 1.5, 2, 4, 8, 24, and 48 hours post morning dose.
(n) Serum for PD (prolactin concentrations) will be obtained:
–
Screening (local laboratory for inclusion/exclusion ONLY).
–
Day -2.
Day 1: Predose, 1, 1.5, 2, 4, and 8, 24 hours post morning dose.
–
Day 7: Predose, 1, 1.5, 2, 4, 8, 24, and 48 hours post morning dose.
(o) 
(p) For GEBT and SmartPill evaluation. On dosing days, the test meal will be administered 1 hour post the AM dose. The test meal will consist of 100 mg 13C–Splatensis, 27 g 
freeze-dried egg mix, 6 saltine crackers, and 180 mL of water. The caloric content of the meal is 238 kcal, and the meal has a balanced composition of 16.9 g carbohydrates, 14.4 g 
protein, and 11.2 g fat.
(q) Lunch will be administered approximately 5 hours post AM dose. If the subject is confined to the clinical research unit (CRU) (optional), dinner will be provided 2-3 hours post 
PM dose. The meals on Day -1, 1, 4 and 7 will be standard. 
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Statistical Analysis Plan Final
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CONFIDENTIAL
Part 2
Part 2 (Treatment E [Periods 1 and 2] and Treatment F)
Day
Day 1
Hours
-1
Predose
0
0.5
1
1.5
2
4
8
24
48
Early
Termina-
tion
Follow-
Up 
Visit (a)
Administrative procedures
Prior and concomitant medication review
Clinical procedures/assessments
---------------------------------Continuous Review-------------------------------------------------
Full physical examination (b)
X
X
X
Semi-recumbent vital signs (heart rate, systolic and diastolic blood pressure)
X (c)
X
X
X
Vital signs (respiratory rate, oral [floor of the mouth]/tympanic temperature)
X (c)
X
X
X
12-lead ECG standard
X (c)
X
X
X
TAK-906 maleate or metoclopramide administration (d)
X
Sliding scale insulin as needed (e)
X
AE Monitoring
-----------------------Continuous Monitoring-------------------------------------------------
Laboratory procedures/assessments
Fingerstick glucose (e)
X-----------------------------------------------------------------------------------------------X
hCG 
X
X
X
PK evaluations
Plasma samples for metoclopramide PK (Group F)
X
X
X
X
X
X
X
X
X
Other
High fat breakfast (Group E) (h)
X
Standard meals (i)
X---------------------------------------------X
(a) Follow-up visit will occur approximately 14 days after the last dose of trial drug received in Part 2 or if the prematurely discontinues at any time during the study. Else, a 7-day 
washout separates each dosing period (ie, fed, fasted) in Part 2 food-effect arm (Group E).
(b) Predose Day 1 physical examination may be done within approximately 48 hours predose Day 1.
(c) Vital signs and 12-lead ECG will be performed within approximately 1 hour predose on Day 1. 
(d) Subjects will be given either a single-dose of 25 mg TAK-906 with a high fat breakfast or in the fasted state (Treatment Group E) or 10 mg metoclopramide (1 hour before test 
meal) (Treatment Group F).TAK-906 or metoclopramide will be administered as a witnessed dose at approximately 0700-0800.
(e) Diabetes mellitus only: If the subject is confined to the CRU, fingerstick glucose measurements will be obtained up to 3 times per day (pre-AM dose, pre-lunch, pre-dinner). At 
all other times (washout and nonconfinement) the subject will obtain a fingerstick glucose measurement pre-breakfast and at bedtime. Pre-test meal values must be below 270 
mg/dL. If glucose is above 270 mg/dL prior to the GEBT, a sliding scale insulin administration should be implemented.
(f) 
 
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Statistical Analysis Plan Final
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CONFIDENTIAL
(g
 
 
(h) Subjects will be given either a single-dose TAK-906 maleate 25 mg between 0700 and 0800 (after at least an 8 hour fast) approximately 30 minutes after the start of a high-fat 
breakfast, or in the fasted state, ie, Period 1 or 2 (Group E). 
(i) If the subject is confined to the CRU, lunch will be administered approximately 5 hours post AM dose, dinner will be provided 2-3 hours post PM dose.
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TAK-906-1002
Page 32 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
Appendix B
Clinical Laboratory Tests and Screening
Chemistry 
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Bicarbonate
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be fractionated
Protein (total)
Hematology
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Urinalysis
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of RBC/high-power field, 
WBC/high-power field, and casts.
Urine Drug Screen
Amphetamines
3,4-methylenedioxy-methamphetamine 
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Alcohol Screen
Subjects will undergo an alcohol test (breathalyzer or urine, at the discretion of the investigator).


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Statistical Analysis Plan Final
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CONFIDENTIAL
Screening - Serum
HIV 
Hepatitis Screen (hepatitis A virus antibody, HBsAg, 
hepatitis C virus antibody)
β–human chorionic gonadotropin (females only)
FSH (females only)
Prolactin 


TAK-906-1002
Page 34 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
Appendix C
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell.
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
<50 mg/dL
>350 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Calcium
Conventional 
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Bicarbonate
Conventional 
<8.0 mEq/L
SI 
<8.0 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


TAK-906-1002
Page 35 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
Appendix D
Criteria for Abnormal Values for Serum Prolactin
Unit
Gender
Normal
Markedly Abnormal Value
ng/mL
Female
≤29.2 
>5x ULN
Male
≤17.7 
>5x ULN


TAK-906-1002
Page 36 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
Appendix E
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Heart Rate
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
oF
<35.6 
<96.1
>37.7
>99.9


TAK-906-1002
Page 37 of 37
Statistical Analysis Plan Final
15 March 2018
CONFIDENTIAL
Appendix F
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤120 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤60 milliseconds
≥120 milliseconds


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