Clinical trial NCT03281577
Conditions: Diabetic Gastroparesis Idiopathic Gastroparesis
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2018-01-02; Completion date: 2019-07-12
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in participants with diabetic or idiopathic gastroparesis assessed by scintigraphy.

Detailed description:
The drug being tested in this study is called TAK-954. TAK-954 is a serotonin (5 HT4) receptor agonist and is being tested to treat people who have diabetic or idiopathic gastroparesis and who previously reported delay in stomach emptying. This study will look at the gastric emptying time of solids in people who take TAK-954 or placebo.

The study will enroll approximately 41 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK-954 0.1 mg
* TAK-954 0.3 mg
* TAK-954 1 mg
* Placebo (dummy inactive solution) - this is a solution that looks like the study drug but has no active ingredient.

This single center trial will be conducted in the United States. The duration of treatment is 3 days and the overall period of evaluation is up to 28 days. The participants will be contacted by telephone (Days 10 to 14) for follow-up assessment. There will be another follow-up phone call for women of childbearing potential (Days 38 to 43).

Arms: arm 1: TAK-954 placebo-matching, 60-minute infusion, intravenously (IV), once daily on Days 1 to 3. arm 2: TAK-954 0.1 mg, 60-minute infusion, IV, once daily on Days 1 to 3. arm 3: TAK-954 1 mg, 60-minute infusion, IV, once daily for up to 3 days. arm 4: TAK-954 1 mg, 60-minute infusion, IV, once daily on Days 1 to 3.
Interventions: intervention 1: TAK-954 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-954 IV infusion. intervention 2: TAK-954 placebo-matching IV infusion.

Protocol documents:
Prot_000.pdf: 



Title: A Dose-Ranging, Randomized, Parallel, Placebo-Controlled Study to Assess the Effect of 
TAK-954 on Gastrointestinal and Colonic Transit in Patients With Diabetic or Idiopathic 
Gastroparesis
NCT Number: NCT03281577
Protocol Approve Date: 19 December 2018
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 (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
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.


1.0 TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Dose-Ranging, Randomized, Parallel, Placebo-Controlled Study to Assess the Effect of 
TAK-954 on Gastrointestinal and Colonic Transit in Patients With Diabetic or Idiopathic 
Gastroparesis
Effect of TAK-954 on Gastrointestinal and Colonic Transit in Diabetic or Idiopathic 
Gastroparesis Patients
Sponsor:
Takeda Development Center Americas, Inc. 
Study Number:
TAK-954-2003
IND Number:
114408
EudraCT Number:
Not Applicable
Compound:
TAK-954
Date:
19 December 2018
Version/Amendment 
Number:
05
Amendment History: 
Date
Amendment Number
Region
28 July 2017
Initial version
Global
06 November 2017
01
Global
28 February 2018
02
Global
26 April 2018
03
Global
11 September 2018
04
Global
19 December 2018
05
Global
Property
or non-commercial use only and subject to the applicable Terms of Use


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Development Center Americas, Inc. (TDC) sponsored investigators per individual 
country requirements will be provided with emergency medical contact information cards to be 
carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance, Takeda Development Center Americas, 
Inc. 
Medical Monitor
(medical advice on protocol and study drug)
Medical Director, Clinical Science
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
Medical Director, Clinical Science
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1.2
Approval 
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also 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, clinical trial 
disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures are provided on the last page of this document.
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ubject to the applicable Terms of Use
PPD


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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 of this 
protocol.
Terms outlined in the study site agreement.
Responsibilities of the Investigator (Appendix A and Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D 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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1.3
Protocol Amendment 05 Summary of Changes
Rationale for Amendment 05
This document describes the changes in reference to the protocol incorporating Amendment 05. 
The primary reason for this amendment is the elimination of 1 dosing arm based on the results of 
the interim analysis. The opportunity was taken to make additional changes.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix F.
Changes in Amendment 05
1. Revised number of subjects based on the findings of the interim analysis.
2. Decreased the number of active treatment arms.
3. Revised the type of vital sign procedures collected and clarified the timing in relation to 
pharmacokinetic (PK) blood draws.
4. Elimination of optional PK samples.
5. Revised the timing of vital sign measurements. 
6. Eliminated instruction of the timing of PK sampling and electrocardiogram procedures.
7. Revised information related to interim analysis.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 05 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
List of Abbreviations ...............................................................................................16
3.3
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Rationale for the Proposed Study.............................................................................20
4.3
Benefit/Risk Profile .................................................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective ..............................................................................................22
5.1.2
Secondary Objectives.........................................................................................22
5.1.3
Exploratory Objectives.......................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoint...............................................................................................22
5.2.2
Secondary Endpoints..........................................................................................22
5.2.3
Safety Endpoints................................................................................................23
5.2.4
Exploratory Endpoints .......................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................24
6.1
Study Design ...........................................................................................................24
6.2
Justification for Study Design, Dose, and Endpoints ................................................28
6.3
Premature Termination or Suspension of Study or Study Site...................................28
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................28
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................29
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................29
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................30
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7.3
Excluded Medications..............................................................................................31
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................33
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................34
8.1
Study Drug and Materials ........................................................................................34
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................34
8.1.1.1
TAK-954.................................................................................................34
8.1.1.2
Ancillary Materials..................................................................................34
8.1.2
Storage...............................................................................................................34
8.1.3
Dose and Regimen .............................................................................................34
8.1.4
Overdose............................................................................................................35
8.2
Study Drug Assignment and Dispensing Procedures ................................................35
8.3
Randomization Code Creation and Storage..............................................................35
8.4
Study Drug Blind Maintenance................................................................................35
8.5
Unblinding Procedure..............................................................................................35
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................36
9.0
STUDY PLAN ..............................................................................................................37
9.1
Study Procedures.....................................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Demographics, Medical History, and Medication History Procedure..................37
9.1.3
Physical Examination Procedure ........................................................................37
9.1.4
Weight, Height and BMI....................................................................................37
9.1.5
Vital Sign Procedure..........................................................................................38
9.1.6
Documentation of Concomitant Medications......................................................38
9.1.7
Documentation of Concurrent Medical Conditions.............................................38
9.1.8
Procedures for Clinical Laboratory Samples.......................................................38
9.1.9
Contraception and Pregnancy Avoidance Procedure...........................................40
9.1.9.1
Male Subjects and Their Female Partners ................................................40
9.1.9.2
Female Subjects and Their Male Partners ................................................40
9.1.9.3
Definitions and Procedures for Contraception and Pregnancy Avoidance.41
9.1.9.4
General Guidance With Respect to the Avoidance of Pregnancy..............43
9.1.10 Pregnancy ..........................................................................................................43
9.1.11 ECG Procedure..................................................................................................43
9.1.12 Scintigraphy Procedure ......................................................................................44
9.1.13 Pharmacogenomic and Biomarker Sample Collection ........................................45
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9.1.13.1
Biomarker Sample Collection..................................................................45
9.1.14 PK Sample Collection and Analysis ...................................................................46
9.1.14.1
Collection of Plasma for PK Sampling.....................................................46
9.1.15 Documentation of Screen Failure .......................................................................47
9.1.16 Documentation of Randomization......................................................................47
9.1.17 Blood Volume....................................................................................................48
9.2
Monitoring Subject Treatment Compliance..............................................................48
9.3
Schedule of Observations and Procedures................................................................48
9.4
Biological Sample Retention and Destruction ..........................................................48
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................50
10.1
Definitions...............................................................................................................50
10.1.1 PTEs..................................................................................................................50
10.1.2 AEs....................................................................................................................50
10.1.3 Additional Points to Consider for PTEs and AEs................................................50
10.1.4 SAEs..................................................................................................................52
10.1.5 Management of Specific AEs.............................................................................53
10.1.5.1
Cardiovascular Disorders.........................................................................53
10.1.5.2
Serotonin Syndrome ................................................................................55
10.1.5.3
AESI .......................................................................................................55
10.1.6 Intensity of PTEs and AEs .................................................................................55
10.1.7 Causality of AEs ................................................................................................56
10.1.8 Relationship to Study Procedures.......................................................................56
10.1.9 Start Date...........................................................................................................56
10.1.10
Stop Date .....................................................................................................56
10.1.11
Frequency ....................................................................................................56
10.1.12
Action Concerning Study Drug ....................................................................56
10.1.13
Outcome.......................................................................................................57
10.2
Procedures...............................................................................................................57
10.2.1 Collection and Reporting of AEs........................................................................57
10.2.1.1
PTE and AE Collection Period.................................................................57
10.2.1.2
PTE and AE Reporting ............................................................................57
10.2.1.3
AEs of Special Interest ............................................................................58
10.2.2 Collection and Reporting of SAEs......................................................................58
10.2.3 Reporting of Abnormal LFTs.............................................................................59
10.3
Follow-up of SAEs ..................................................................................................59
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10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................59
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................60
12.0
DATA HANDLING AND RECORDKEEPING............................................................61
12.1
CRFs (Electronic and Paper)....................................................................................61
12.2
Record Retention .....................................................................................................61
13.0
STATISTICAL METHODS..........................................................................................63
13.1
Statistical and Analytical Plans ................................................................................63
13.1.1 Analysis Sets......................................................................................................63
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................63
13.1.3 Pharmacokinetic Analysis ..................................................................................63
13.1.4 PD Analysis .......................................................................................................64
13.1.5 Biomarkers ........................................................................................................65
13.1.6 Safety Analysis ..................................................................................................65
13.1.7 Other Analyses...................................................................................................65
13.2
Interim Analysis and Criteria for Early Termination ................................................65
13.3
Determination of Sample Size..................................................................................66
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................67
14.1
Study-Site Monitoring Visits ...................................................................................67
14.2
Protocol Deviations..................................................................................................67
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................67
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................68
15.1
IRB..........................................................................................................................68
15.2
Subject Information, Informed Consent, and Subject Authorization .........................68
15.3
Subject Confidentiality ............................................................................................70
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................70
15.4.1 Publication and Disclosure.................................................................................70
15.4.2 Clinical Trial Registration..................................................................................70
15.4.3 Clinical Trial Results Disclosure ........................................................................71
15.5
Insurance and Compensation for Injury....................................................................71
16.0
REFERENCES..............................................................................................................72
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications........................................................................................32
Table 9.a
Clinical Laboratory Tests...................................................................................39
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Table 9.b
Primary Specimen Collections ...........................................................................47
Table 10.a
Takeda Medically Significant AE List................................................................53
Table 13.a
Summary of Detectable Effect Sizes for PD Endpoints.......................................66
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................25
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................73
Appendix B
Responsibilities of the Investigator.....................................................................75
Appendix C
Elements of the Subject Informed Consent.........................................................77
Appendix D
Investigator Consent to Use of Personal Information..........................................80
Appendix E
Hepatic Function Categories Based on Child-Pugh Score...................................81
Appendix F
Detailed Descriptions of Amendments to Text ...................................................82
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc. 
Compound:
TAK-954
Title of Protocol: A Dose-Ranging, Randomized, Parallel, 
Placebo-Controlled Study to Assess the Effect of TAK-954 
on Gastrointestinal and Colonic Transit in Patients With 
Diabetic or Idiopathic Gastroparesis
IND No.: 114408
EudraCT No.:
Not applicable
Study Number: 2003
Phase: 2a
Study Design:
This is a phase 2a, dose-ranging, randomized, parallel group, double-blind, placebo-controlled study evaluating the 
effects of TAK-954 on gastrointestinal (GI) and colonic transit in diabetic subjects reporting symptoms of 
gastroparesis with previously documented delay in gastric emptying or in subjects with diagnosis of idiopathic 
gastroparesis. The study will evaluate 12 subjects per treatment group. 
This study consists of 3 periods and a Follow-up: a Screening Visit, a Baseline Period (between Day -14 and 
Day -1), Treatment Period (Days 1 to 4), and Follow-up Phone Call (Days 10 to 14). 
Subjects will have an initial Screening Visit, then will undergo a baseline gastric emptying assessment with 
scintigraphy scans acquired at 0, 1, 2, 3 and 4 hours after radiolabeled meal, between Day -14 and Day -1 (Baseline 
Visit). The Screening and Baseline Visits may be performed on the same day.
If eligibility criteria are fulfilled, subjects will be randomized on Day 1 to TAK-954 0.1, 0.3, or 1 mg, or placebo. 
Based upon the results of the preplanned interim analysis, the number of active treatment arms has been decreased 
from 3 to 2. The specific dose deleted is not specified in order to maintain the blind of the study team. This change 
was not necessitated by safety findings.
Subjects will receive TAK-954 or placebo as a 60-minute intravenous (IV) infusion (at any time in the morning 
prior to 12:00) once a day for 3 days starting on Day 1. Following the infusion on Day 2, subjects will undergo 
scintigraphic assessment of gastric, small bowel, and colonic transit of solids over a 48-hour time period while on 
treatment.
The subjects will have pharmacokinetic (PK) samples collected as follows:

Day 1: prior to dosing (0 hour), 1 (end of infusion), 2, and 4 hours after start of infusion. 

Day 2: prior to dosing (0 hour), 1 (end of infusion), 2, 5, 7, and 9 hours after the start of the infusion. 

Day 3: prior to dosing (0 hour), 1 (end of infusion) and 2 hours after start of infusion.

Day 4: 25 hours after the start of the infusion on Day 3 (48 hours after the administration of the radiolabeled 
meal on Day 2, same time as the 48-hour geometric center measurement).
All participating subjects will have a 6-hour Holter monitor placed at the Baseline Visit. On Day 1, subjects will 
have continuous monitoring with a Holter monitor which will be placed prior to the first dose until the morning of 
Day 3. 12-lead ECG will be performed on Days 1, 2, and 3 prior to each IV infusion; within 30 minutes postinfusion 
and prior to discharge; and at the Final Visit on Day 4 or Early Termination Visit. In addition, a 12-lead ECG will be 
performed when needed, if a subject develops symptoms or clinical signs suggestive of cardiovascular origin (eg, 
dizziness, lightheadedness, chest pain, chest heaviness, palpitations, shortness of breath, tachycardia).
During the study, subjects will complete a daily diary to record their bowel habits. The subjects will assess their 
global GI symptom score using the GCSI at Screening. The On-study Bowel Habit Diary Card will be dispensed at 
Screening, to be completed daily from Screening and through the Treatment Period. The completed Bowel Habit 
Diary Card will be collected at the conclusion of the study.
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Primary Objective:
To evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in subjects with diabetic or 
idiopathic gastroparesis assessed by scintigraphy.
Secondary Objectives:
1.
To evaluate the PD effects of TAK-954 on intestinal and colonic transit time assessed by scintigraphy.
2.
To evaluate the PK of TAK-954 in subjects with gastroparesis.
3.
To assess the safety and tolerability of multiple doses of TAK-954.
Subject Population: Diabetic subjects reporting symptoms of gastroparesis with a previously documented delay in 
stomach emptying or subjects with a diagnosis of idiopathic gastroparesis.
Number of Subjects:
Approximately 36 to 41 subjects (maximum of 12 per 
group)
Number of Sites: 
Estimated total: 1 site in the United States
Dose Level(s):
TAK-954 0.1, 0.3, and 1 mg once daily (QD)
Placebo
Route of Administration:
TAK-954 (IV)
Placebo (IV)
Duration of Treatment:
3 days
Period of Evaluation:
Up to 28 days
Main Criteria for Inclusion: 
Males and nonpregnant, nonbreastfeeding females who are aged 18 to 65 years, inclusive, with a body mass index 
(BMI) ≥16 and ≤40 kg/m2. Subjects must have diabetes mellitus with symptoms of gastroparesis and previously 
documented gastric emptying delay or previously documented idiopathic gastroparesis in the last 5 years. 
Main Criteria for Exclusion:
Subjects who:

Have glycosylated hemoglobin (HbA1c) >12%.

Have other structural diseases/conditions that affect the GI system.

Are unable to withdraw drugs known to alter GI transit 48 hours prior to the study.

Have clinically significant abnormal baseline safety labs.

Have clinical evidence of significant cardiovascular, respiratory, moderate or severe renal insufficiency, 
hematological, neurological, or psychiatric disease, or other disease that interferes with the objectives of the 
study. 

Have preexisting hepatic disease that meets Child-Pugh Class B (moderate; total score 7 to 9 points) or C 
(severe; total score 10 to 15 points), see Appendix E.

Are without known preexisting hepatic disease who have 1 or more of the following:

AST or ALT >2 times the ULN.

Bilirubin >1.5 times the ULN unless due to Gilbert’s syndrome.

International normalized ratio (INR) >1.5 unless on anticoagulation therapy.

Have QTcF (QT interval with Fredericia correction method) interval ≥460 msec or with other factors that 
increase the risk of QT prolongation or arrhythmic events at screening. Note: Subjects with bundle branch block 
and a prolonged QTc interval, or with QTcF between 450 and 460 msec, should be reviewed by the medical 
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monitor for potential inclusion.

Have cardiac history that includes conditions requiring heart rate control (eg, atrial fibrillation, atrial flutter). 

Have second or third degree atrioventricular (AV) block; AV disassociation; >5 beats of non-sustained VT at a 
rate >120 bpm; ECG changes consistent with acute myocardial ischemia or infarction.

If female, are pregnant or lactating or intending to become pregnant before participating in this study, during the 
study, and 4 to 5 days (5 half-lives) PLUS 30 days after last dose of the study drug; or intending to donate ova 
during such time period.

Are considered by the investigator to be alcoholics not in remission or known substance abusers. Have 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).
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is half-emptying time (T1/2) of gastric emptying of solids.
The secondary endpoints for this study are:

Colonic geometric center at 4, 24, and 48 hours after radiolabeled meal.

Colonic filling at 6 hours (measure of small bowel transit time) after radiolabeled meal.

T1/2 of ascending colon emptying.

The plasma PK parameters (area under the concentration-time curve during a dosing interval [AUCτ], maximum 
observed concentration [Cmax], and observed concentration at the end of a dosing interval [Ctrough]) of 
TAK-954.
The safety endpoints for this study are:

The percentage of subjects who experience at least 1 treatment-emergent adverse event. 

The percentage of subjects who discontinue due to an adverse event (AE). 

The incidence of subjects who meet the markedly abnormal criteria for safety laboratory tests postdose. 

The incidence of subjects who meet the markedly abnormal criteria for vital sign measurements postdose.

The percentage of subjects who meet the markedly abnormal criteria for safety 12-lead ECG parameters and 
Holter monitor postdose.
Statistical Considerations:
The effects of the TAK-954 treatment on the primary PD endpoint will be assessed using analysis of covariance 
(ANCOVA). The secondary response measures will also be assessed using ANCOVA (with suitable transformation 
for skewness in the distributions of measured volumes), and, if necessary, nonparametric methods will be used. The 
covariates considered for inclusion in the analyses will be age, gender, BMI, and the baseline measurement of the 
respective PD measure. Two-sided 95% CI will be presented for the comparison of each dose of TAK-954 against 
placebo, both multiplicity adjusted and unadjusted CIs will be presented. 
Information on the global score using the GCSI, as well as bowel movement frequency per day and average stool 
consistency on the Bristol stool form scale, will be tabulated and analyzed respectively. 
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Sample Size Justification: Below summarizes data for the primary and secondary PD response measures and uses 
the (relative) percent coefficient of variation, (%CV) to estimate the effect size detectable with 80% power based on 
a 2 sample z-test (ie, assuming the variation values are known) at a two-sided alpha level of 0.05. The effect size is 
the difference in group means as a percentage of the overall mean for each response and assumes 12 subjects per 
group. The ANCOVA should provide 80% power to detect similar (pairwise) differences using a pooled estimate of 
variation across all 3 groups and potentially even smaller effect sizes by adjusting for important covariates. An 
effect size of at least 30% for the primary endpoint is considered to be clinically important. The data from the 
scintigraphic transit studies are unpublished but based on the same methods proposed for this study.
Assuming n=12/Group 4-GROUP DESIGN (Based on ANCOVA α=0.05)
Response Type
Mean
SD
%CV
Effect Size (%)
Detectable with 80%
Power (=0.05)
Gastric emptying of solids T1/2 min 
(N=319)
122
29.8
24.5
34.2
Colonic filling at 6 h, % (N=63)
44
29
66
79
Geometric center at 24 h (N=220)
2.4
0.9
36
52
Ascending colon T1/2 h (N=50)
15.0
8.0
53
63
An interim analysis was conducted when approximately half of the subjects have completed the study. Efficacy and 
safety data was reviewed to determine if the study should be modified based on the interim analysis results. 
An executive committee within Takeda composed of a senior clinician, a senior statistician, a senior clinical 
pharmacologist, and a senior pharmacovigilance scientist not involved in the study have reviewed the interim 
analysis results and made recommendations for changes to the study. All members of the study team and the 
investigative team will remain blinded to treatment arm assignment and treatment arm results until the completion of 
the study.
Based upon the results of the preplanned interim analysis, 1 of the TAK-954 doses was dropped. The specific dose 
dropped is not specified in order to maintain the blind of the study team. The sample size for the remaining 
treatment arms will not change.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
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3.2
List of Abbreviations
5HT4
serotonin
99mTc
technetium-99m
111In
indium chloride isotope
AC
ascending
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC24,ss
area under the concentration-time curve from time 0 to time 24, at steady state
AUCτ
area under the concentration-time curve during a dosing interval
AV
atrioventricular
BP
blood pressure
BMI
body mass index
%CV
percent coefficient of variation
Cmax
maximum observed concentration
Cmax,ss 
maximum observed concentration during a dosing interval, at steady state
Ctrough
observed concentration at the end of a dosing interval
CYP
cytochrome P450
DC
Descending colon
eCRF
electronic case report form
ECG
electrocardiogram
EFI
enteral feeding intolerance
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GCSI
Gastroparesis Cardinal Symptom Index 
GGT
γ-glutamyl transferase
GI
gastrointestinal
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
INR
international normalized ratio
IRB
institutional review board
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IUD
intrauterine device
IV
intravenous
kcal
kilocalorie 
LFT(s)
liver function test(s)
MTD
maximum tolerated dose
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect-level
PD
pharmacodynamic(s)
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PPS
per protocol set
RS
rectosigmoid colon
PTE
pretreatment event
QD
once daily
QTc
corrected QT interval
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SUSARs
suspected unexpected serious adverse reactions
SVT
supraventricular tachycardia
T1/2
half-emptying time
TC
transverse colon
ULN
upper limit of normal
VT
ventricular tachycardia
3.3
Corporate Identification
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
TAK-954 is a highly selective and potent 5-HT4 receptor agonist that has shown prokinetic 
activity throughout the gastrointestinal (GI) tract in experimental models and is in development 
for short-term (acute) use in the treatment of critically ill patients with enteral feeding intolerance 
(EFI). Critically ill patients who require enteral feeding frequently have reduced GI motility 
including delayed gastric emptying, develop enteral feeding intolerance, which can lead to 
several complications including not meeting daily calorie and protein requirements [1]. 
Malnutrition in these patients is associated with impairment of immunological function, 
increased risk of infection, prolongation of mechanical ventilation, increased length of intensive 
care unit and hospital stay, and ultimately higher mortality [2,3].
Nonclinical studies completed to date include intravenous (IV) and oral single-dose studies in 
rats, oral single-dose studies in dogs, and oral 28-day and 13-week repeat-dose studies in rats and 
dogs. TAK-954 was also tested in vitro and in vivo genotoxicity studies, embryo-fetal toxicity 
studies in rats and rabbits, and ex vivo and in vivo local tolerance studies. Toxicokinetic analysis 
of TAK-954 plasma levels was conducted in the Good Laboratory Practice repeat-dose studies. 
Studies of TAK-954 on central nervous system and respiration showed no effect at clinically 
relevant doses. In the cardiovascular safety pharmacology study in dogs, dose-dependent 
increases in mean heart rate (HR) and non-dose-dependent increases in diastolic blood pressure 
and mean arterial blood pressure were observed (61-fold margin at dog no-observed-effect level 
(NOEL) versus healthy human maximum observed concentration [Cmax] at 1 mg, IV 
[extrapolation based on 2x0.5 mg, IV pharmacokinetics (PK); assumes linear PK between 
0.5 and 1 mg dose]). 
TAK-954 is a substrate of cytochrome P450 (CYP) 3A4, CYP2D6, CYP2C9/19, and 
P-glycoprotein. TAK-954 had no significant inhibitory effect on the activities of major human 
CYPs 1A2, 2C9, 2C19, 2D6, and 3A in human liver microsomes. No inhibitory effect of the 
metabolites, THRX-513466 and THRX-913682, were observed on the metabolic activities of 
CYP1A2, CYP2C19, and CYP3A, and only moderate inhibition (up to 42%) was observed on 
the metabolic activities of CYP2C9 and CYP2D6 at high TAK-954 concentrations of 10 µM. 
TAK-954 is moderately protein bound, exhibiting concentration-independent binding.
In repeat-dose toxicity studies, the key adverse findings attributed to TAK-954 administration 
were decreased body weight gains and food consumption at higher doses in rats, dogs, and 
rabbits, effects that were dose-limiting in these species. In the 13-week dog study, an 
approximately 10.5% increase in the QT interval with Fridericia correction method (QTcF) was 
noted only on Day 28 in males receiving 30 mg/kg/day (160-fold margin at dog NOEL at 
10 mg/kg/day versus healthy human Cmax at 1 mg, IV [extrapolation based on 2x0.5 mg, IV 
Cmax]). Other notable effects of TAK-954 observed in the rat toxicity studies included 
phospholipidosis in the lung and vacuoles in scattered thyroid follicular cells of rats, and 
vacuolated macrophages in the spleen and an increase in the degree of mammary gland 
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development in female rats; these findings were all reversible but did not reach full resolution at 
the end of the recovery period (468-fold margin at rat no-observed-adverse-effect level 
[NOAEL] versus healthy human area under the concentration-time curve from 0 to 24 hours 
[AUC24] at 1 mg, IV [extrapolation based on 2x0.5 mg, IV AUC24]). TAK-954 did not exhibit 
genotoxic potential. The embryo-fetal toxicity studies in rats and rabbits demonstrated embryo-
fetal effects characterized by lower fetal weights and increased skeletal variations (decreased 
ossification) limited to maternally toxic doses (250-fold margin at rabbit NOAEL versus healthy 
human AUC24 at 1 mg, IV [extrapolation based on 2x0.5 mg, IV AUC24]).
TAK-954 was well-tolerated in local tolerance studies at concentrations up to 20 µg/mL and did 
not cause hemolysis or flocculation in rat, dog, or human whole blood. 
TAK-954 has been evaluated in 4 clinical studies to date: 3 phase 1 studies in healthy subjects, 
and an exploratory phase 2 study in critically ill patients with enteral feeding intolerance (EFI).
After single ascending oral doses (0.1 to 20 mg) of TAK-954 in healthy subjects, the maximum 
tolerated dose (MTD) dose was 10 mg and resulted in a Cmax of 94.4 ng/mL and area under the 
concentration time-curve from time 0 to infinity of 1017 ng•hr/mL. After multiple ascending oral 
doses (0.2 to 10 mg) once daily (QD) of TAK-954 in healthy subjects, the MTD dose was 5 mg 
and resulted in a maximum observed concentration during a dosing interval, at steady state 
(Cmax,ss) of 27.72 ng/mL and area under the concentration-time curve from 0 to 24 hours at 
steady state (AUC24,ss) of 386.515 ng•hr/mL. Cmax and the area under the concentration-time 
curve (AUC) increased in a roughly dose-proportional manner. TAK-954 was not extensively 
converted to either metabolite (THRX-513466 or THRX-913682), as assessed by circulating 
levels in plasma and urine.
After multiple daily IV infusion dosing in healthy subjects, mean TAK-954 Cmax,ss was 7.07 and 
7.6 ng/mL in Cohorts 1 (0.5 mg QD over 5 days) and 2 (0.1 mg on Day 1 and 0.5 mg QD Days 2 
to 5), respectively. Mean TAK-954 AUC24,ss was 51.0 and 63.3 ng.h/mL in Cohorts 1 and 2, 
respectively. TAK-954 steady state was achieved by Day 3, with mean half-life (t1/2) values 
ranging from 18.0 to 18.9 hours on Day 5. The increase in Day 1 exposure from the 0.1 to 
0.5 mg IV dose was approximately dose proportional. Based on the principle of superposition, 
the predicted Cmax,ss and AUC24,ss for TAK-954 1 mg IV dosing were 15.2 ng/mL and 
126.6 ng.h/mL, respectively, which are approximately 2 to 3-fold lower comparing to multiple 
oral doses of 5 mg. The mean amount of TAK-954 excreted unchanged in urine on Day 5 ranged 
from 27.7% to 31.6%. In subjects who were critically ill and received 0.5 mg by IV infusion, the 
PK exposure was approximately 30% lower to that observed in healthy subjects.
After multiple oral doses in healthy subjects, TAK-954 was generally well tolerated at doses up 
to 5 mg QD for 10 days. There were no serious adverse events (SAEs) and the overall incidence 
of adverse events (AEs) reported for the TAK-954 dose groups was similar to that for the 
placebo group. All AEs were mild or moderate. The most commonly reported treatment-related 
AEs in TAK-954 subjects overall were headache and diarrhea. No dose-related trends were 
evident in the AE data across the 0.2, 1, or 5 mg dose groups, but 2 of 3 subjects receiving 10 mg 
were discontinued because of an AE (mild intermittent atrioventricular dissociation which 
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resolved without intervention). There were no safety signals in the clinical laboratory or 
respiratory rate data after multiple dose administration. Mean blood pressure (BP) and HR 
remained in the normal range for all groups throughout the study. However, there was a trend 
toward lower BP and elevated HR in the standing position for TAK-954 subjects, but no dose 
response was apparent. In addition, there was 1 AE related to BP (orthostatic hypotension in a 
subject who received 5 mg TAK-954).
Evidence of GI prokinetic activity in healthy subjects (increased bowel movement frequency, 
looser stool consistency, and decreased time to first bowel movement) was observed at all dose 
levels after receiving single and multiple doses (oral and IV). In 7 subjects who were critically 
ill, scintigraphy data qualitatively suggested TAK-954 decreases gastric emptying time following 
a liquid meal.
The purpose of this dose-ranging, randomized, parallel group, double-blind, placebo-controlled 
study is to evaluate the pharmacodynamic (PD) effects of TAK-954 on gastric, intestinal, and 
colonic transit in diabetic subjects reporting symptoms of gastroparesis with previously
documented delay in stomach emptying, or in subjects with a diagnosis of idiopathic 
gastroparesis.
Please refer to the TAK-954 Investigator’s Brochure for complete information on the 
investigational product.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirements.
4.2
Rationale for the Proposed Study
Gastroparesis is a syndrome characterized by delayed gastric emptying in the absence of 
mechanical obstruction of the stomach. The cardinal symptoms include postprandial fullness 
(early satiety), nausea, vomiting, pain, and bloating. Gastroparesis occurs in several clinical 
settings, particularly as a complication of diabetes mellitus, but also as a complication of upper 
GI surgery, neurological disease, collagen vascular disorders, viral infections, drugs, and so on. 
In the majority of cases, no underlying cause is found and gastroparesis is termed idiopathic. 
Several abnormalities in diabetes might result in gastric motor dysfunction including autonomic 
neuropathy, enteric neuropathy involving excitatory and inhibitory nerves, abnormalities of the 
interstitial cells of Cajal and acute fluctuations in blood glucose among others [4]. 
The underlying mechanism of delayed gastric emptying is common to both patients with 
gastroparesis and EFI, and the same products have been successfully studied and utilized in both 
populations to promote gastric emptying. This study will evaluate the prokinetic effect of 
TAK-954 on gastric emptying, intestinal and colonic transit in subjects with previously 
documented delay in gastric emptying.
Phase 1 studies have demonstrated acceptable PK characteristics and TAK-954 was well 
tolerated at all doses studied in the completed phase 1 and 2a studies. The TAK-954 IV doses to 
be used in the study, 0.1, 0.3 and 1 mg, were selected based on safety, tolerability, PK, and PD 
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(bowel movement, gastric emptying time, and HR) data from the healthy and critically ill subject 
studies. Based on a TAK-954 preliminary population-PK model using data from Phase 1 studies 
and in-vitro receptor saturation data, predicted subjects’ trough 5-HT4 receptor occupancy at 
steady state is estimated to be approximately 30%, 50% and 80% for 0.1, 0.3 and 1 mg doses, 
respectively. The dose range, 0.1, 0.3 and 1 mg, is expected to span the anticipated 
pharmacologically active dose range and is potentially considered well within the safety margin.
4.3
Benefit/Risk Profile 
There is no expected clinical benefit to the study participants. Potential risks are based on 
TAK-954 clinical findings, the mechanism of action, nonclinical findings and the route of 
administration. The study involves the use of radiation that is within limits permissible for 
healthy volunteers and hence patients.
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). The principal mitigation for these risks includes appropriate 
selection of the study populations, the Clinical Research and Trials Unit setting, which permits 
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 study.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to evaluate the dose-dependent effects of TAK-954 on 
gastric emptying time of solids in subjects with diabetic or idiopathic gastroparesis assessed by 
scintigraphy.
5.1.2
Secondary Objectives
The secondary objectives of this study are to:
Evaluate the PD effects of TAK-954 on intestinal and colonic transit time assessed by 
scintigraphy.
Evaluate PK of TAK-954 in subjects with gastroparesis.
Assess the safety and tolerability of multiple doses of TAK-954.
5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint for this study is half-emptying time (T1/2) of gastric emptying of solids.
5.2.2
Secondary Endpoints
The secondary endpoints for this study are: 
Colonic geometric center at 4, 24, and 48 hours after the radiolabeled meal.
Colonic filling at 6 hours (measure of small bowel transit time) after the radiolabeled meal.
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T1/2 of ascending colon emptying.
The following PK parameters of TAK-954:
–
Area under the concentration-time curve during a dosing interval (AUCτ), Cmax, and
observed concentration at the end of a dosing interval (Ctrough).
5.2.3
Safety Endpoints
The safety endpoints for this study are:

The percentage of subjects who experience at least 1 treatment-emergent adverse event. 

The percentage of subjects who discontinue due to an AE. 
The incidence of subjects who meet the markedly abnormal criteria for safety laboratory tests 
postdose. 
The incidence of subjects who meet the markedly abnormal criteria for vital sign measurements
postdose.
The percentage of subjects who meet the markedly abnormal criteria for safety 12-lead ECG 
parameters and Holter monitor postdose.
5.2.4
Exploratory Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 2a dose-ranging, randomized, parallel group, double-blind, placebo-controlled 
study evaluating the effects of TAK-954 on gastric, small bowel, and colonic transit in diabetic 
subjects reporting symptoms of gastroparesis with previously documented delay in stomach 
emptying or in subjects with diagnosis of idiopathic gastroparesis. Twelve subjects per treatment 
group in diabetic subjects with symptoms of gastroparesis and previously documented delay in 
stomach emptying or in subjects with diagnosis of idiopathic gastroparesis will be evaluated. 
This study consists of 3 periods and a Follow-up: a Screening Period, Baseline Period (between 
Day -14 and Day -1), Treatment Period (Days 1 to 4), and a Follow-up Phone Call (Days10 -
14). Women of childbearing potential will receive an additional Follow-up Phone Call 
(Days 38-43). 
Subjects will have an initial Screening Visit, then will undergo a baseline gastric emptying 
assessment with scintigraphy scans acquired at 0, 1, 2, 3, and 4 hours after radiolabeled meal, 
between Day -14 and Day -1 (Baseline Visit). The Screening and Baseline Visits may be 
performed on the same day. Within 48 hours prior to baseline scintigraphy, female subjects must 
have a negative pregnancy test. 
If eligibility criteria are fulfilled, subjects will be randomized on Day 1 to TAK-954 0.1, 0.3, or 1 
mg, or placebo. Subjects will receive TAK-954 or placebo as a 60-minute intravenous (IV) 
infusion (at any time in the morning prior to 12:00) once a day (QD) for 3 days starting on Day 
1. Following the TAK-954 infusion on Day 2, subjects will undergo scintigraphic assessment of 
gastric, small bowel, and colonic transit of solids during the Treatment Period.
At each visit, the fasting state of the subjects (8 hours) will be confirmed and fasting (finger 
stick) blood glucose obtained. 
During the study, subjects will complete a daily diary to record their bowel habits. The subjects 
will assess their global GI symptom score using the GCSI at Screening. The On-Study Bowel 
Habit Diary Card will be dispensed at Screening to be completed daily from Screening and 
through the Treatment Period. The completed Bowel Habit Diary Card will be collected at the 
conclusion of the study.
The subjects will have PK samples collected as described in Section 9.1.14.1.
All participating subjects will have a 6-hour Holter monitor placed at the Baseline Visit. On 
Day 1, subjects will have continuous ECG monitoring for up to 4 hours after the infusion, and 
continuous monitoring with a Holter monitor which will be placed prior to the first dose on 
Day 1 until the morning of Day 3. 
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Participants will undergo follow-up safety monitoring by phone 7-10 days post last treatment 
dose. The study will be considered completed after the last subject’s Follow-up Phone Call.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
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Figure 6.a
Schematic of Study Design (continued)
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Figure 6.a
Schematic of Study Design (continued)
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6.2
Justification for Study Design, Dose, and Endpoints
The TAK-954 IV doses to be used in the study, 0.1, 0.3 and 1 mg, were selected based on safety, 
tolerability, PK and PD (bowel movement, gastric emptying time, HR) data from the healthy and 
critically ill subject studies. Based on unbound TAK-954 plasma concentrations using a 
preliminary population-PK model and in-vitro receptor saturation, predicted subjects’ trough 
5-HT4 receptor occupancy at steady state are estimated to be approximately 30%, 50% and 80% 
for 0.1, 0.3 and 1 mg doses, respectively. The dose range, 0.1, 0.3 and 1 mg, is expected to span 
the anticipated pharmacologically active dose range and is considered well within the safety 
margin.
Measurement of gastric emptying of solids as measured by T1/2 is endorsed by national societies 
[9] for use in clinical practice to identify gastric motor function abnormalities as in conditions 
associated with slow or accelerated gastric emptying, to investigate pathophysiological 
mechanisms that may be associated with patients’ symptoms or syndromes, and to evaluate the 
effects of treatment such as prokinetic agents [4]. Therefore scintigraphy assessment of gastric 
emptying is the most appropriate tool to evaluate the pharmacodynamic properties of TAK-954 
in upper GI motility and to assess its potential in both gastroparesis and enteral feeding 
intolerance.[4]
The study’s secondary endpoints include colonic geometric center at 4, 24, and 48 as a measure 
of colonic transit time and colonic filling at 6 hours as an indirect measure of intestinal transit 
time that will help to obtain a complete picture of the prokinetic effect of TAK-954 by assessing 
its effects on the lower GI tract. This assessment is relevant not only because it can help to 
evaluate TAK-954’s potential application in other conditions associated with delayed intestinal 
motility such as postoperative ileus, intestinal pseudo obstruction or constipation; but also 
because it can help to determine the right dose for use in future trials in critically ill patients at 
high risk of malnutrition and EFI as accelerated bowel and colonic transit time can increase the 
risk of diarrhea and malabsorption.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the TAK-954, such that the risk is no 
longer acceptable for subjects participating in the study.
Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety.
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6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. The subject has diabetes mellitus with symptoms of gastroparesis and previously documented 
gastric emptying delay or previously documented idiopathic gastroparesis in the last 5 years.
4. The subject is a male or nonpregnant, nonbreastfeeding female and aged 18 to 65 years, 
inclusive.
5. The subject has a body mass index (BMI) ≥16 and ≤40 kg/m2 at the Screening Visit. 
6. A female subject of childbearing potential* must agree to use highly effective contraception 
during the course of the study. 
*Definitions and highly effective methods of contraception are defined in 
Section 9.1.9 and reporting responsibilities are defined in Section 9.1.10.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has participated in another interventional clinical study within the past 30 days.
2. The subject is an immediate family member, investigational team member, or is in a 
dependent relationship with an investigational team member who is involved in conduct of 
this study (eg, spouse, parent, child, sibling) or may consent under duress.
3. The subject has HbA1c >12%.
4. The subject has other structural diseases/conditions that affect the GI system.
5. The subject has a history of hypersensitivity or allergies to TAK-954.
6. The subject is unable to withdraw any of the following medications listed in Table 7.a
48 hours prior to the study.
7. The subject has a clinically significant abnormal baseline safety laboratory value.
8. The subject has preexisting hepatic disease that meets Child-Pugh Class B (moderate; total 
score 7 to 9 points) or C (severe; total score 10 to 15 points), see Appendix E. 
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9. Subjects without known preexisting hepatic disease who have 1 or more of the following:

AST or ALT >2 times the ULN.

Bilirubin >1.5 times the ULN unless due to Gilbert’s syndrome.

International normalized ratio (INR) >1.5 unless on anticoagulation therapy.
10. The subject has QTcF interval ≥460 msec or with other factors that increase the risk of QT 
prolongation or arrhythmic events at screening. Note: Subjects with bundle branch block and 
a prolonged QTc interval, or with QTcF between 450 and 460 msec, should be reviewed by 
the medical monitor for potential inclusion. 
11. Subjects who have second or third degree atrioventricular (AV) block; AV disassociation; 
>5 beats of non-sustained VT at a rate >120 bpm; ECG changes consistent with acute 
myocardial ischemia or infarction.
12. The subject has a cardiac history that includes conditions requiring HR control (eg, atrial 
fibrillation, atrial flutter, ventricular tachycardia, or other tachyarrhythmias).
13. The subject has clinical evidence (including physical examination, ECG, clinical laboratory 
value and review of the medical history) of significant cardiovascular, respiratory, moderate 
or severe renal insufficiency (creatinine clearance ≤60 mL/min), hematological, neurological, 
psychiatric, or other disease that interferes with the objectives of the study.
14. If female, are pregnant or lactating or intending to become pregnant before participating in 
this study, during the study, and within 4 to 5 days (5 half-lives) PLUS 30 days after last dose 
of the study drug; or intending to donate ova during such time period.
15. If male, the subject intends to donate sperm during the course of this study or for 4 to 5 days 
(5 half-lives) PLUS 30 days thereafter.
16. The subject is considered by the investigator to be an alcoholic not in remission or known 
substance abuser; have 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).
17. A subject, who in the determination of the investigator, possesses any condition that the 
investigator believes would put the subject at risk or would preclude the subject from 
successfully completing all aspects of the study.
7.3
Excluded Medications
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. Use of excluded agents (prescription or 
nonprescription) is outline in Table 7.a.
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Table 7.a
Excluded Medications
Medication
Drugs known to alter GI transit including laxatives, 
magnesium or aluminum-containing antacids, 
prokinetics, erythromycin, narcotics, anticholinergics, 
tricyclic antidepressants.
Monoamine oxidase inhibitors.
Selective serotonin reuptake inhibitors: escitalopram, 
citalopram, fluoxetine, sertraline, paroxetine, 
fluvoxamine, and newer antidepressants.
Serotonin and norepinephrine reuptake inhibitors: 
venlafaxine, duloxetine, desvenlafaxine, milnacipran, 
levomilnacipran.
Analgesic drugs including opiates, nonsteroidal 
antiinflamatories, cyclooxygenase-2 inhibitors.
Benzodiazepines.
Antidiabetes treatment with pramlintide or glucagon-
like peptide-1 receptor agonists.
N-methyl-D-aspartate receptor antagonist. phencyclidine, 
ketamine, tiletamine, methoxetamine, dextromethorphan, 
pethidine, levorphanol, methadone, dextropropoxyphene, 
tramadol, ketobemidone.
Gamma-aminobutyric acidergic (GABAergic) agents: 
bicuculline, securinine, metrazol, flumazenil.
5-HT agonist.
Note: Low stable doses of thyroid replacement, estrogen replacement, aspirin for cardioprotection, and birth control 
pills or depot injections; metformin, dipeptidyl peptidase-IV inhibitors, and insulin for diabetes are permissible.
7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form eCRF using the following categories. For screen 
failure subjects, refer to Section 9.1.15.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or 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 PTE or AE.
2. Liver Function Test (LFT) Abnormalities
Study 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 9.1.8), if the following circumstances occur at any time 
during study drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (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 INR 
>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%).
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3. Significant protocol deviation. The discovery (postrandomization) 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 after 3 attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented in the 
subject’s source documents. 
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
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 due to 
an AE should not be recorded in the “voluntary withdrawal” category.
6. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
7. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.4. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects will 
not be replaced.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.
8.1.1.1
TAK-954
The drug product, TAK-954 Injection (Concentrate for Solution for Infusion), consists of a clear 
colorless solution of TAK-954 free base in clear Type I glass vials fitted with a rubber stopper 
and sealed with an aluminum cap. The drug product is formulated as 0.1 mg/mL of TAK-954 
free base equivalent dissolved in water for injection, adjusted to pH 5.0 with hydrochloric acid 
and/or sodium hydroxide. Each glass vial contains 5.5 mL of sterile TAK-954 solution designed 
to deliver nominally 5.0 mL of the solution. The drug product solution is intended to be diluted 
to the required concentration with a diluent for IV infusion. The placebo IV infusion solution is 
the diluent only and prepared in the same manner as the active. Please see the pharmacy manual 
for preparation and administration instructions.
TAK-954 cartons and vials will be affixed with clinical labels that are in accordance with all 
regulatory requirements.
8.1.1.2
Ancillary Materials 
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.
8.1.2
Storage
The required storage condition for TAK-954 study drug is refrigeration between 2°C and 8°C. 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature 
log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The subjects will be randomized to TAK-954 0.1, 0.3, or 1 mg; or placebo and will receive 
TAK-954 or placebo as a 60-minutes infusion IV once a day for 3 days starting on Day 1. The 
number of active treatment arms decreased based upon the prespecified interim analysis. To 
maintain the blinding of the study team, the specific treatment arm is not identified. This change 
was not necessitated by safety findings.
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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
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 database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive their treatment according to the randomization schedule 
allocated to the study site.
8.3
Randomization Code Creation and Storage
Randomization personnel or the designee of the sponsor will generate the randomization 
table/schedule and will provide it to the site pharmacist prior to the start of this study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Study Drug Blind Maintenance 
The study drug blind is maintained through a randomization schedule held by authorized persons 
only.
8.5
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. All study assessments and 
causality assessment should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor should be contacted before the study drug 
blind is broken to discuss the need for unblinding.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study. 
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8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed locally.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee or destroyed locally.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs
received, dispensed and remaining at the conclusion of the study. For all study sites, the local 
country sponsor personnel or designee will provide appropriate documentation that must be 
completed for clinical study drug accountability, return and/or destruction.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, ethnicity, race as 
described by the subject, height, weight, and smoking status of the subject at Screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 48 hours prior to signing of informed 
consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) GI system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system looking for hyperreflexia, hypertonicity and 
clonus; (10) lymph nodes; and (11) other. All subsequent physical examinations should assess 
clinically significant changes from the assessment prior to first dose examination.
9.1.4
Weight, Height and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height is recorded in centimeters without decimal places. Weight is collected in kilograms 
(kg) with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
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Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. However, if the BMI is used as entry criteria based on 
40 kg/m2 cut-off point, then this determination must be made after rounding. 
9.1.5
Vital Sign Procedure
Vital signs will include sitting/supine blood pressure (systolic and diastolic, resting more than 
5 minutes), and pulse (beats per minute).
When vital signs are scheduled at the same time as PK blood draws, the PK blood draw will take 
priority and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at screening examination, according to the judgment of 
the investigator. The condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be given in the laboratory manual.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with 
differentials
Hemoglobin
Hematocrit
Platelets
ALT
AST
Albumin
Alkaline phosphatase
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
γ-glutamyl transferase (GGT)
Potassium
Sodium
Glucose
HbA1c (a)
TSH(a)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
Microscopic analysis (RBC/high power field, WBC/high 
power field, epithelial cells, casts, etc.) to be performed if 
abnormal.
Other:
Serum
Urine
Coagulation
Hepatitis panel, including HBsAg 
and anti-HCV
Beta hCG (female subjects only)
INR
Female subjects only:
Beta human chorionic gonadotropin 
([hCG] for pregnancy)
Follicle-stimulating hormone
(FSH)
If menopause is suspected.
HbsAg=hepatitis B virus surface antigen, HCV=hepatitis C virus, RBC=red blood cell, WBC=white blood cell.
(a) HbA1c and TSH to be collected at Screening only.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 3 days and preferably within 48-72 hours after the abnormality was noted. (Refer to 
Section 7.4 and Section 10.2.3 for the appropriate guidance on reporting abnormal LFTs.)
If ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the medical monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3).
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9.1.9
Contraception and Pregnancy Avoidance Procedure
9.1.9.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 4 to 5 days 
(5 half-lives) PLUS 30 days after last dose of study drug, nonsterilized** male subjects who are 
sexually active with a female partner of childbearing potential* must use barrier contraception 
(eg, condom with or without spermicidal cream or jelly). In addition, they must be advised not to 
donate sperm during this period. Females of childbearing potential who are partners of male 
subjects are also advised to use additional contraception as shown in the list containing highly 
effective contraception below.
9.1.9.2
Female Subjects and Their Male Partners
Animal studies for TAK-954 have demonstrated embryotoxicity and there is a lack of adequate 
reproductive toxicity data in humans; therefore, female subjects should be instructed to use
highly effective methods of contraception.
From signing of informed consent, throughout the duration of the study, and for 4 to 5 days 
(5 half-lives) PLUS 30 days after last dose of study drug, female subjects of childbearing 
potential* who are sexually active with a nonsterilized male partner** must use a highly 
effective method of contraception (from the list below). 
Methods: 
Combined (estrogen and progestogen) hormonal contraception associated with inhibition of 
ovulation.
–
Oral. 
–
Intravaginal.
–
Transdermal. 
Progestogen-only hormonal contraception associated with inhibition of ovulation.
–
Oral. 
–
Injectable.
–
Implantable.
IUD.
Bilateral tubal occlusion.
In addition, they must be advised not to donate ova during this period.
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9.1.9.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
*A woman is considered a woman of childbearing potential (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 postmenopausal state in 
younger women (eg, those < 45 years old) or women who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
**Sterilized males should be at least 1 year postbilateral 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 
included, the only acceptable methods of contraception are: 
Nonhormonal Methods: 
–
IUD.
–
Bilateral tubal occlusion.
Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound and concomitant medications, which may reduce the efficacy of 
the contraception method (Evaluate on compound-by-compound and 
protocol-by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug in combination with a 
barrier method (male condom, female condom, or diaphragm);

Oral.
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
Injectable.

Implantable.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, donation of ova, and 
sperm donation during the course of the study.
4. During the course of the study, regular serum/urine hCG pregnancy tests will be performed 
only for women of childbearing potential and all subjects (male and female) 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 pregnant partners.
c) Assessment of subject compliance through questions such as:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles 
a pregnancy test must be performed if the answer is “yes”).
iv. Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses); a negative serum hCG pregnancy test prior to the first dose of study 
medication (Day 1; if a negative serum hCG pregnancy test was obtained on Day -1, then the 
serum pregnancy test on Day 1 can be discontinued); and a negative urine pregnancy test 
within 48 hours prior to consuming a radiolabeled meal. A serum hCG test may substitute for 
a urine pregnancy test as long as the timing of the test as required is appropriately 
maintained. 
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9.1.9.4
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 partners of childbearing potential.
Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
–
Is there a chance you could be pregnant?
9.1.10 Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and TAK-954 
should be immediately discontinued. In addition, any pregnancies in the partner of a male subject 
during the study or for 4 to 5 days (5 half-lives) PLUS 30 days after the last dose, should also be 
recorded following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, from Day 1 up to 4 to 5 days 
(5 half-lives) PLUS 30 days of the last dose of active study drug, the pregnancy should be 
reported immediately, using a pregnancy notification form, to the contact listed in Section 1.0.
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. Subjects randomized to placebo need not be followed.
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 female 
subject/female partner of the 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 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.
9.1.11 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. 12-lead ECG will be 
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performed on Days 1, 2, and 3 prior to each IV infusion; within 30 minutes postinfusion and 
prior to discharge; and at the Final Visit on Day 4 or Early Termination Visit. In addition, a 
12-lead ECG will be performed when needed, if a subject develops symptoms or clinical signs 
suggestive of cardiovascular origin (eg, dizziness, lightheadedness, chest pain, chest heaviness, 
palpitations, shortness of breath, tachycardia).
The time that the ECG was performed will be recorded. The following parameters will be 
recorded on the eCRF from the subject’s ECG trace: heart rate, RR interval, PR interval, QT 
interval, QRS interval, and QT and QTcF. 
All participating subjects will have a 6-hour Holter monitor placed at the Baseline Visit. On 
Day 1, subjects will have continuous monitoring with a Holter monitor which will be placed 
prior to the first dose until the morning of Day 3. Interpretation of the Holter monitor recording 
will be performed by a Mayo cardiologist.
9.1.12 Scintigraphy Procedure
An adaptation of the Mayo Clinic’s established scintigraphic method will be used to measure GI 
transit. A radiolabeled meal of 99mTc (technetium-99m)-sulfur colloid added to 2 scrambled eggs 
will then be eaten with 1 slice of whole wheat bread and 1 glass of skim milk. This meal 
facilitates measurement of gastric and small bowel transit. 111In (indium chloride isotope)-
absorbed on activated charcoal particles will be delivered to the colon by means of a 
methacrylate-coated, delayed-release capsule.
At the Baseline Visit (between Days -14 and -1), subjects will ingest the radiolabeled 
standardized test meal followed by scans after ingestion at 0, 1, 2, 3 and 4 hour timepoints. 
On Day 2, subjects will ingest the radiolabeled (111In) charcoal capsule just prior to the 
60-minute infusion of TAK-954. The radiolabeled breakfast for scintigraphic study will be given 
at the end of the TAK-954 infusion. Relative to the time of completion of the breakfast meal 
ingestion, abdominal images are obtained pre-meal, immediately following the radiolabeled 
meal, and every 30 minutes following the meal for the first 4 hours and then hourly until 8 hours 
(5 and 9 hours post start of infusion on Day 2), then at 24 and 48 hour timepoints post breakfast 
meal on Day 2 (1 hour and 25 hours post start of infusion on Day 3). Following the first day of 
study drug administration on Day 1, subjects will return the next 2 days (Days 2 and 3) for IV 
administration of study medication. On Days 3 and 4, subjects will return in the morning for the 
24- and 48-hour abdominal images, respectively. The performance characteristics of this test are 
summarized in Scintigraphy: Gastric Emptying, Small Bowel, and Colonic Transit SOPs by 
Enteric Physiology and Imaging Facility. 
All subjects on treatment will consume the same test meal as above followed by standardized test 
meals at lunch and afternoon snack at 4 and 8 hours after the radio labeled meal, respectively. 
Prior to the 4-hour scan on Day 2, a standard meal (chicken, potato, pudding “Stanghellini” 
meal), 550 kilocalorie (kcal) will be ingested. Hourly images will be taken until 8 hours 
post-radiolabeled meal, when the second standard roast beef sandwich “Greydanus” 750 kcal 
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snack is ingested 15 minutes prior to the scheduled 8-hour scan. The subject will leave the study 
center at the end of the afternoon. They will be asked to return the following days fasting 
(Days 3 and 4), for IV administration of study medication (Day 3 only) and the image at 24 
(Day 3) and 48 hours (Day 4) after the ingestion of radiolabeled meal on Day 2.
All efforts will be made to obtain the scintigraphy scans at the exact nominal time relative to 
dosing. However, samples obtained within 10 to 15 minutes of the nominal time from dosing 
will not be captured as a protocol deviation, as long as the exact time of dosing and time of scan 
is noted on eCRF.
9.1.13 Pharmacogenomic and Biomarker Sample Collection
9.1.13.1
Biomarker Sample Collection
Proper
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9.1.14 PK Sample Collection and Analysis
9.1.14.1
Collection of Plasma for PK Sampling
The subjects will have PK samples collected as follows:
Days 1: prior to dosing (0 hour), 1 (end of infusion), 2, and 4 hours after start of infusion. 
Day 2: prior to dosing (0 hour), 1 (end of infusion), 2, 5, 7, and 9 hours after the start of the 
infusion. 
Day 3: prior to dosing (0 hour), 1 (end of infusion), and 2 hours after start of infusion.
Day 4: 25 hours after the start of infusion on Day 3 (48 hours after the administration of the 
radiolabeled meal and capsule on Day 2, same time as the 48-hour geometric center 
measurement).
PK samples collected during the infusion will be drawn from the opposite arm from where the 
infusion is delivered. All efforts will be made to obtain the PK and PD samples at the exact 
nominal time relative to dosing. However, samples obtained within 10% of the nominal time 
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from dosing will not be captured as a protocol deviation, as long as the exact date and time of 
dosing (start and ending of infusion) and the sampling collection is noted on eCRF.
Primary specimen collection parameters are provided in Table 9.b.
Table 9.b
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Description of Intended Use
Sample Collection
Plasma sample for TAK-954 PK
Plasma
Pharmacokinetic 
measurements
Mandatory
If indicated, these collected samples may also be assayed for metabolites and/or additional PD 
markers.
9.1.15 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is withdrawn at the Screening Visit, the investigator should complete the eCRF.
The primary reason for screen failure is recorded in the eCRF using the following categories:
PTE/AE.
Did not meet inclusion criteria or did meet exclusion criteria. <specify reason>
Significant protocol deviation.
Lost to follow-up.
Voluntary withdrawal (specify reason).
Study termination.
Other study-specific.
Other (specify reason).
Subject identification numbers assigned to subjects who fail screening should not be reused.
9.1.16 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
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If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
On Day 1, if they fulfill eligibility criteria, the subjects will be randomized to TAK-954 (0.1, 0.3, 
or 1 mg) or placebo.
9.1.17 Blood Volume 
The maximum volume of blood at any single day is approximately 50 mL, and the approximate 
total volume of blood for the study is 250 mL.
Direct venipuncture is the preferred method of blood collection. 
9.2
Monitoring Subject Treatment Compliance
All supplies used to administer study drug to the subject will be recorded on the eCRFs.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.4
Biological Sample Retention and Destruction
In this study, blood, and blood derived samples for biomarker measurement will be collected as 
described in Section 6.1. Any leftover biomarker samples if not utilized will be preserved and 
retained at sponsor selected for long term storage facility for up to 15 years from the end of 
study. After that time, the samples will be destroyed.
The pharmacogenomic (PGx) samples will be initially stored at a vendor/comparable lab, under 
contract to Takeda, with validated procedures in place, and then preserved and retained at a 
sponsor-selected long-term storage facility, for up to but not longer than 15 years, from the end 
of the study when the study report is signed, or if less, the maximum period permitted under 
applicable law or until consent is withdrawn. 
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code 
that is different from the code attached to the health information and other clinical test results 
collected in the trial. The sample and data are linked to personal health information with code 
numbers; the samples are stripped of all personal identifying information but a key linking the 
samples to clinical analysis data exists. This link means that the subject may be identified but 
only indirectly. The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their 
consent at any time and request disposal of a stored sample. Any remaining sample that can be 
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identified as coming from the subject will be destroyed. The trial doctor and sponsor may 
continue to use and distribute any information and test results gathered before the request to 
withdraw.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or AEs.)
Necessitate therapeutic intervention.
Require an invasive diagnostic procedure.
Require discontinuation or a change in dose of study drug or a concomitant medication.
Be considered unfavorable by the investigator for any reason.
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs 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 a PTE(s) or as an AE(s).
Laboratory values and ECG findings:
Changes in laboratory values or ECG findings are only considered to be PTEs or 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 or ECG retest and/or continued monitoring of an abnormal value or finding is not 
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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 a PTE or as an AE.
Pre-existing conditions:
Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication of 
such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). 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 concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious or severe in nature. I Investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (eg “worsening of…”).
If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be recorded as a PTE/AE if occurring to a greater extent 
to that which would be expected. Investigators should ensure that the AE term recorded captures 
the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:
If the subject experiences a worsening or complication of a PTE after the start of study drug, the 
worsening or complication should be recorded as an AE. Investigators should ensure that the AE 
term recorded captures the change in the PTE (eg, “worsening of…”).
If the subject experiences a worsening or complication of an AE after any change in study drug, 
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 intensity of AEs /serious PTEs:
If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed 
consent are not considered PTEs or 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 
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condition should be recorded as a PTE or 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 PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness and 
lack of therapeutic efficacy.
Overdose:
Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested 
side effects will be considered PTEs or AEs and will be recorded on the AE page of the eCRF.
10.1.4 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. Leads to 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
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure 
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered 
as “Important Medical Events” satisfying SAE reporting requirements. 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Management of Specific AEs
10.1.5.1
Cardiovascular Disorders
Cardiovascular events:
Tegaserod, a nonselective 5-HT4 agonist, was withdrawn from the market in 2007 based on 
pooled clinical trial results that suggested increased risk of cardiovascular ischemic events. 
Alternatively, TAK-954, highly selective 5-HT4 agonist, did not demonstrate significant AEs 
related to cardiovascular events in studies to date. In TAK-954 clinical studies, 1 subject 
received TAK-954 0.5 mg IV in the intensive care unit (ICU) following an emergency 
evacuation of a spontaneous posterior fossa intraparenchymal hemorrhage. This patient died due 
to her underlying admitting diagnosis. 
The medical monitor should be contacted within 24 hours if a subject develops cardiovascular 
events that include ischemic heart disease, cerebrovascular accident (eg, transient ischemic 
attack and stroke), venous or arterial thromboembolic events, and heart failure. 
QT Prolongation
Cisapride, a nonselective 5-HT4 agonist and a potent human ether-à-go-go–related gene blocker, 
was withdrawn from the market due to the risk of prolonged QT interval and sudden death. 
In TAK-954 clinical studies, only 1 subject in Study 0082 had QTcF over 450 msec. This subject 
received TAK-954 0.5 mg IV was in the ICU following an emergency evacuation of a 
spontaneous posterior fossa intraparenchymal hemorrhage. She had medical history of atrial 
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fibrillation on warfarin, mitral valve replacement, and biventricular pacemaker, and on 
Screening, her QTcF was 461 msec. She had a maximum QTcF of 496 msec on Day 1 and she 
was not treated for this finding.
If a subject develops QT prolongation (QTcF) longer than 480 msec, study drug should be 
discontinued, levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range, and concomitant therapies 
should be reviewed and adjusted as appropriate for medications with known QT prolonging 
effects. In addition, the medical monitor should be contacted within 24 hours. Heart-rate 
corrected QT interval will be calculated using Fredericia’s formula (QTcF=QT/RR1/3). 
AV Dissociation/Heart Block
In Study 0061, 2 subjects receiving TAK-954 10 mg orally developed intermittent mild AEs of 
AV dissociation. The finding resolved without treatment. 
If subjects develop new onset first degree heart block, medical monitor will need to be contacted 
to discuss within 24 hours. Treatment with study drug should be discontinued with the 
occurrence of any second or third degree heart block and the medical monitor should be 
contacted within 24 hours.
Treatments with study drug may be continued in second degree heart block Mobitz I 
(Wenckebach) after medical monitor review.
Supraventricular Tachycardia (SVT)
In Study 0061, there was a trend toward lower blood pressure and elevated HR in the standing 
position for TAK-954 subjects, but no dose response was apparent. One subject (Study 0095, 
TAK-954 0.5 mg dose) had the AE of postural tachycardia reported on Day 1, with HR values in 
the standing position ranging from 100 to 116 bpm from 1 to 4 hours postdose. No other subject 
had HR values that were reported as AEs.
Treatment should be discontinued if a subject develops SVT at rest irrespective of the 
seriousness and the medical monitor should be contacted within 24 hours.
Hypotension
Asymptomatic increases in both supine and standing HR were observed at all doses of TAK-954, 
and mean changes in supine and standing blood pressure were variable with no discernible 
pattern across the dose ranges. The dose escalation in the single ascending dose study was 
stopped at 20 mg, according to the protocol-specified stopping rules, because of the occurrence 
of 2 AEs of moderate orthostatic hypotension.
If subjects develop significant hypotension, treatment with study drug should be permanently 
discontinued.
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10.1.5.2 Serotonin Syndrome
Serotonin syndrome, a potentially life threatening adverse drug reaction, may result from drugs 
that increase the serotonergic activity in the central nervous system. The most commonly 
implicated classes of drugs are selective serotonin reuptake inhibitors. The clinical features may 
include agitation, confusion, diarrhea, hyperthermia, tachycardia, hypertension, mydriasis, 
hypertonicity, and hyperreflexia.
If a subject develops any of the following clinical features (Hunter’s criteria):

Spontaneous clonus.

Inducible clonus PLUS agitation or diaphoresis.

Ocular clonus PLUS agitation or diaphoresis.

Tremor PLUS hyperreflexia.

Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus.
Discontinue treatment with study drug. In addition, review the subject medications and 
discontinue any medication(s) that may be associated with serotonin syndrome. Suspected 
serotonin syndrome should be reported to the sponsor as an SAE with 24 hours.
Should any of these events occur in a subject, study drug should be discontinued.
10.1.5.3 AESI
An AE of Special Interest (serious or nonserious) is 1 of scientific and medical concern specific 
to the compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. If there are any significant cardiovascular events, 
please contact the medical monitor to discuss management of these events.
10.1.6 Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
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10.1.7 Causality of AEs
The relationship of each AE to study drug(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 possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications 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.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Drug 
Drug withdrawn – a study drug is stopped due to the particular AE.
Dose not changed – the particular AE did not require stopping a study drug.
Unknown – only to be used if it has not been possible to determine what action has been taken.
Not applicable – a study drug was stopped for a reason other than the particular AE eg, the study 
has been terminated, the subject died, dosing with study drug was already stopped before the 
onset of the AE.
Dose reduced – the dose was reduced due to the particular AE.
Dose increased – the dose was increased due to the particular AE.
Dose interrupted – the dose was interrupted due to the particular AE.
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10.1.13
Outcome
Recovered/resolved – Subject returned to first assessment status with respect to the AE/PTE.
Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE 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 got worse than when it started; is an irreversible congenital anomaly; the subject 
died from another cause with the particular AE/PTE state remaining “Not recovered/not 
resolved”.
Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with some 
persisting paresis.
Fatal – the AEs/PTEs which are considered as the cause of death. 
Unknown – the course of the AE/PTE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (Day 1) or 
until screen failure. For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug 
Day 1). Routine collection of AEs will continue until the Follow-up Visit.
10.2.1.2
PTE and AE Reporting
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 a 
serious PTE 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. Non-serious PTEs, related or unrelated to the study procedure, need not to 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 drug 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 PTEs and AEs will be documented in the PTE/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:
1. Event term.
2. Start and stop date.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
10.2.1.3
AEs of Special Interest
AEs of special interest have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
An AE of special interest (serious or non-serious) is 1 of scientific and medical concern specific 
to the compound or program for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
The investigator should submit the original copy of the SAE form to the sponsor.
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 Serious PTEs will follow the procedure described for SAEs.
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10.2.3 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 10.2.2. 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 or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information 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.
10.3.1 Safety Reporting to Investigators, IRBs, 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, including investigators and 
IRBs. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited report 
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 a 
study drug/sponsor supplied drug or that would be sufficient to consider changes in the study 
drug/sponsor supplied drug administration or in the overall conduct of the study. The study site 
also will forward a copy of all expedited reports to his or her IRB.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study 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 to eCRFs 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 
e-sign 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 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, or sign and seal, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. 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. 
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 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 
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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in International Conference on Harmonisation (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 study site agreement between 
the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
13.1.1 Analysis Sets
Full Analysis Set: The full analysis set (FAS) will include all subjects randomized. Subjects in 
this set will be analyzed according to the original randomization. This will be the main analysis 
set for efficacy analyses.
Per Protocol Set: The per protocol set (PPS) analysis set is a subset of the FAS. The PPS
consists of all subjects who do not violate the terms of the protocol in a way that would 
significantly impact the efficacy assessment. All decisions to exclude subjects from the PPS
dataset will be made prior to the unblinding of the study and subject to clinical review. This 
analysis set will be for efficacy analyses only and can be considered as a sensitivity analysis in 
support of the primary analysis based on the FAS.
Safety Set: The safety set (SAF) will include all subjects who have received at least 1 dose of 
study drug. Subjects in this set will be analyzed according to the treatment they actually 
received. This analysis set will be used for safety analyses only.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by each treatment group and 
overall. Summary statistics (N, mean, SD, median, minimum, and maximum) will be generated 
for continuous variables (eg, age and weight) 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 characteristics data will be listed.
13.1.3 Pharmacokinetic Analysis
PK parameters will be determined from the concentration-time data for all evaluable subjects 
using non-compartmental analysis. Actual sampling times, rather than scheduled sampling times, 
will be used in all PK computations involving sampling times for plasma PK parameters. 
For TAK-954, the following PK parameters including, but not limited to, will be calculated as 
appropriate:
Day 1: AUCτ, Cmax.
Day 2: AUCτ, Cmax, Ctrough.
Day 3: AUCτ, Cmax, Ctrough.
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Additional PK parameters may be calculated as appropriate. More detailed information will be 
given in the clinical pharmacology analysis plan.
13.1.4 PD Analysis
The PD effect of TAK-954 will be assessed using a number of scintigraphic parameters.
Primary PD endpoint
The primary PD endpoint will be the T1/2 of gastric emptying of solids. Geometric mean of 
counts in anterior and posterior gastric regions of interest will be used to estimate by power 
exponential analysis, the proportionate emptying over time of counts from 99mTc solids and 111In 
from the stomach. Gastric emptying from the power exponential analysis for the post injection 
period will be calculated and compared for the different treatments. The primary endpoint will be 
analyzed using analysis of covariance (ANCOVA) methods. The covariates considered for 
inclusion in the analyses will be gastroparesis type (diabetic or idiopathic), age, gender, BMI, 
and the baseline measurement of gastric emptying T1/2. Dunnett’s test will be used to compare 
each treatment arm to placebo. Multiplicity adjusted and unadjusted 95% 2-sided CIs will be 
presented.
TheT1/2 of gastric emptying of solids will be estimated by the linear interpolation using the slope 
of the 2 data points before and after 50% has emptied from the stomach. If less than 50% empty 
at 4 hours, the 3 data points at 180, 210, and 240 minutes will be used to project the time the T1/2 
value.
Secondary PD endpoints
The secondary PD endpoints will be:
Colonic geometric center at 4, 24, and 48 hours after the radiolabeled meal.
Colonic filling at 6 hours (measure of small bowel transit time) after the radiolabeled meal.
T1/2 of ascending colonemptying.
Colonic geometric center at 4, 24, and 48 hours post meal will be estimated using geometric 
mean of counts in ascending, transverse, descending and rectosigmoid colon and stool (weighted 
by factors of 1 to 5, respectively). The geometric center is the weighted average of counts in the 
different colonic regions: ascending (AC), transverse (TC), descending (DC), rectosigmoid (RS), 
and stool. At any time, the portion of colonic counts in each colonic region is multiplied by its 
weighting factors as follows: 
(%AC x 1 + %TC x 2 + %DC x 3 + %RS x 4 + %stool x 5)/100 = geometric center
Thus, a high geometric center implies faster colonic transit. A geometric center of 1 implies that 
all isotope is in the ascending colon, and a geometric center of 5 implies that all isotope is in the 
stool. 
Colonic filling at 6 hours post meal will be estimated by determining the amount of identified 
99mTc -labeled solid meal within the colon at 6 hours with the value corrected for downscatter of 
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radioactivity from the 111Indium chloride isotope located within the same area appearing within 
the technetium window of analysis.
T1/2 of ascending colon emptying will be estimated by power exponential analysis of the 
proportionate emptying over time of counts from the colon. The primary data for this analysis 
will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly 
scans on the first day of transit measurement and the 24 hour data. The T1/2 of ascending colon 
emptying is also estimated by plotting the activity-time curve for percent residing in the 
ascending colon; linear interpolation is used to connect points.
The secondary endpoints will also be assessed using an ANCOVA model. The covariates 
considered for inclusion in the analyses will be gastroparesis type (diabetic or idiopathic), age, 
gender, BMI, and the baseline measurement of the respective endpoint. The data may be 
transformed to correct for non-normality in the distributions of measured variables. If necessary, 
non-parametric ANCOVA will be used.
13.1.5 Biomarkers
Descriptive statistics, graphical methods, and statistical modeling as appropriate will be used to 
explore the relationship between baseline levels/response and the levels of various biomarkers. 
13.1.6 Safety Analysis
AEs will be summarized using the safety analysis set. No statistical testing or inferential 
statistics will be generated. All AEs will be coded using MedDRA. Data will be summarized 
using preferred term and primary system organ class.
Vital signs, ECGs, and laboratory parameters will also be tabulated.
13.1.7 Other Analyses
Patient Reported Outcomes:
Information on the global score using the GCSI, as well as bowel movement frequency per day 
and average stool consistency on the Bristol stool form scale, will be tabulated and analyzed 
respectively.
13.2
Interim Analysis and Criteria for Early Termination
An interim analysis was conducted when approximately half of the subjects have completed the 
study. Efficacy and safety data was reviewed to determine if the study should be modified based 
on the interim analysis results. 
An executive committee within Takeda composed of a senior clinician, a senior statistician, a 
senior clinical pharmacologist, and a senior pharmacovigilance scientist not involved in the study 
have reviewed the interim analysis results and made recommendations for changes to the study. 
All members of the study team and the investigative team will remain blinded to treatment arm 
assignment and treatment arm results until the completion of the study.
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Based upon the results of the preplanned interim analysis, 1 of the TAK-954 doses was dropped. 
The specific dose dropped is not specified in order to maintain the blind of the study team. The 
sample size for the remaining treatment arms will not change.
13.3
Determination of Sample Size
Table 13.a below summarizes data for the primary response measures and uses the percent 
coefficient of variation, (%CV) to estimate the effect size detectable with 80% power based on a 
2 sample z-test (ie, assuming the variation values are known) at a 2-sided alpha level of 0.05. 
The effect size is the difference in group means as a percentage of the overall mean for each 
response and assumes 12 subjects per group. Based on data acquired using the same methods in 
the laboratory, the sample size of 12 subjects per group provides 80% power to detect 
approximately 30% changes in the primary endpoints of the study: gastric emptying, and overall 
colonic transit. This magnitude of change is considered clinically significant. The ANCOVA 
should provide 80% power to detect similar (pairwise) differences using a pooled estimate of 
variation across all 3 groups and potentially even smaller effect sizes by adjusting for important 
covariates. The data from the scintigraphic transit studies are unpublished but based on the same 
methods proposed for this study.
Table 13.a
Summary of Detectable Effect Sizes for PD Endpoints
Assuming n=12/Group in Each of the Dose Groups
Response Type
Mean
SD
%CV
Effect Size (%) †
Gastric emptying of solids T1/2 min (n=319)
122
29.8
24.5
34.2
Colonic filling at 6 h, % (n=63)
44
29
66
79
GC at 24 h (n=220)
2.4
0.9
36
52
Ascending colon T1/2 h (n=50)
15.0
8.0
53
63
GC= geometric center, h=hour, min=minute.
† Detectable with 80% power, =0.05.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
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 guarantees access to source documents by the sponsor or its designee (contract 
research organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information, 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.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB, as required) to determine the appropriate course of action. There 
will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB, as 
required). 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. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol. 
14.3
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 14.1.
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15.0
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 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.
15.1
IRB
IRBs 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. If any member of the IRB 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 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 for approval. The IRB’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. The IRB 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 notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation. Until the site receives notification no 
protocol activities, including screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB 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, and submission of the investigator’s final status report to IRB. All IRB 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 and sponsor.
15.2
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 
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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 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 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.
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.
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.
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Subjects who consented and provided a pharmacogenomic sample for DNA analysis can 
withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal.
15.3
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 subject 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 the monitor or the sponsor’s designee, 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 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 15.2).
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).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 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 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.
15.4.2 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 American investigators), country, 
and recruiting status will be registered and available for public viewing. 
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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. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
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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16.0
REFERENCES
1. Barton RG. Nutrition support in critical illness. Nutr Clin Pract 1994;9(4):127-39.
2. Harrington L. Nutrition in critically ill adults: key processes and outcomes. Crit Care Nurs 
Clin North Am 2004;16(4):459-65.
3. Slone DS. Nutritional support of the critically ill and injured patient. Crit Care Clin 
2004;20(1):135-57.
4. Camilleri M, Iturrino J, Bharucha AE, Burton D, Shin A, Jeong ID, et al. Performance 
characteristics of scintigraphic measurement of gastric emptying of solids in healthy 
participants. Neurogastroenterol Motil 2012;24(12):1076-e562.
5. Li Y, Nie Y, Xie J, Tang W, Liang P, Sha W, et al. The association of serotonin transporter 
genetic polymorphisms and irritable bowel syndrome and its influence on tegaserod 
treatment in Chinese patients. Dig Dis Sci 2007;52(11):2942-9.
6. Uppalapati SS, Ramzan Z, Fisher RS, Parkman HP. Factors contributing to hospitalization 
for gastroparesis exacerbations. Dig Dis Sci 2009;54(11):2404-9.
7. Bharadwaj S, Meka K, Tandon P, Rathur A, Rivas JM, Vallabh H, et al. Management of 
gastroparesis-associated malnutrition. J Dig Dis 2016;17(5):285-94.
8. Gao LB, Tian H, Wang XG, Yu XF, Guan Y, Chen ML, et al. Early enteral and parenteral 
nutritional support after hepatectomy in patients with hepatic carcinoma: a systematic review 
and meta-analysis. Onco Targets Ther 2015;8:623-31.
9. Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, et al. Consensus 
recommendations for gastric emptying scintigraphy: a joint report of the American 
Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J 
Gastroenterol 2008;103(3):753-63.
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Appendix A
Schedule of Study Procedures
Screening 
(a)
Baseline 
(a)
Treatment Days
Final Visit or 
Early
Termination 
Visit (b)
Follow-up 
Phone Call
Study Day
1
2
3
4
Visit Windows (Days):
-14 to -1
-14 to -1
10 - 14
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics 
X
Physical examination (c)
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
Weight, height, and BMI
X
Concomitant medications
X
X
X
X
X
X
X
Clinical laboratory tests (e)
X
X
X
X
X
Fasting (finger stick) blood glucose (f)
X
X
X
X
12-lead ECG (g)
X
X
X
X
X
6-hour Holter monitor 
X
Holter monitoring (h)
X
X
X
PTE
X
X
Serum pregnancy test (hCG) (i)
X
X
Urine pregnancy test (j)
X
Randomization
X
Medication history
X
X
Concurrent medical conditions
X
X
Plasma sample for TAK-954 PK (k)
X
X
X
X
Gastroparesis Cardinal Symptom Index
X
Bowel Habit Diary Card 
X
X
X
X
X
X
Hepatitis panel
X
Scintigraphy (o)
X
X
X
X (p)
Study drug dosing
X
X
X
AE assessment
X
X
X
X
X
X
Radiolabeled meals (q)
X
X
Charcoal administration (r)
X
Footnotes are on last table page.
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Study No. TAK-954-2003
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Protocol Incorporating Amendment No. 05
19 December 2018
(a) Screening and Baseline Visit procedures may be done on the same day.
(b) Conduct Final Visit procedures for subjects discontinued early per Section 7.5. The end of study is defined as the date of the 
last visit (Day 4) of the last subject undergoing the study unless the study is stopped earlier by sponsor.
(c) Physical examination will be conducted prior to dosing on Days 1, 2, and 3.
(d) Vital signs will be collected at Screening and Baseline, and on Days 1, 2, 3 and 4 upon arrival and departure from the Clinical 
Research and Trials Unit, and on Day 1, 2, and 3 prior to dosing (0 hour), 1 (end of infusion), and 2 hours after start of infusion.
(e) Hematology, serum chemistries, and urinalysis tests. HbA1c and TSH will be assessed only at Screening.
(f) If the Screening and Baseline Visits are combined (same day), a fasting blood glucose (finger stick) will not be performed if 
blood glucose is performed.
(g) 12-lead ECG will be performed prior to each IV infusion, within 30 minutes post infusion, and at discharge on Days 1, 2, and 
3; and at the Final Visit on Day 4 or Early Termination Visit. In addition, a 12-lead ECG will be performed when needed, if a 
subject develops symptoms or clinical signs suggestive of cardiovascular origin (eg, dizziness, lightheadedness, chest pain, chest 
heaviness, palpitations, shortness of breath, tachycardia).
(h) Holter monitor will be placed prior to dosing on Day 1 until the morning of Day 3.
(i) Women of childbearing potential. If a negative serum hCG pregnancy test was obtained on Day -1, then the serum pregnancy 
test on Day 1 can be discontinued. 
(j) Urine pregnancy test will be conducted within 48 hours prior to consuming a radiolabeled meal in women of childbearing 
potential if screening serum pregnancy test was not completed within these 48 hours. 
(k) PK timepoints will be collected as follows: 
Day 1: prior to dosing (0 hour), 1 (end of infusion), 2, and 4 hours after start of infusion.
Day 2: prior to dosing (0 hour,), 1 (end of infusion), 2, 5, 7, and 9 hours after the start of the infusion.
Day 3: prior to dosing (0 hour), 1 (end of infusion), 2, and hours after start of infusion.
Day 4: 25 hours post start of infusion on Day 3 (48 hours after the administration of the radiolabeled meal on Day 2, same time as 
the 48-hour geometric center measurement).
(l) 
 
(m) 
 
 
.
(n)
 
 
.
(o) Scintigraphy: 
Baseline at 0, 1, 2, 3, and 4 hours (240 min) post-radiolabeled meal on Days -14 to Day -1.
Day 2 at every 0.5 hour for first 4 hours post radiolabeled meal, ie, 5 hours post start of infusion, then hourly until 9 hours post 
start of infusion (8 hours post radiolabeled meal) on Day 3 at 1 hour post start of infusion (24 hours post radiolabeled meal on 
Day 2), and on Day 4 at 25 hours post start of infusion on Day 3 (48 hours post radiolabeled meal on Day 2).
(p) Scintigraphy will not be performed if this is an Early Termination Visit.
(q) Radiolabeled meals administered at Baseline (between Day -14 and Day -1) and Day 2 at the end of infusion (1 hour post start 
infusion).
(r) Radiolabeled charcoal capsule administered on Day 2 at predose (within 5 minutes of start of infusion).
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TAK-954
Study No. TAK-954-2003
Page 75 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
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 who will assist in the protocol.
3. 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.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, and 
issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. 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. 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.
9. 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 
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.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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Study No. TAK-954-2003
Page 76 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Study No. TAK-954-2003
Page 77 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
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, 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 and whom to contact in the event of a 
research-related injury to the subject.
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Study No. TAK-954-2003
Page 78 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject or the 
subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
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 pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or 
provided as a separate document) describing to the subject the contemplated and permissible 
uses and disclosures of the subject’s personal information (including personal health 
information) for purposes of conducting the study. The subject authorization must contain the 
following statements regarding the uses and disclosures of the subject’s personal 
information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
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Study No. TAK-954-2003
Page 79 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study, and for 4 to 5 days (5 half-
lives) PLUS 30 days after last dose. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. 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. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 4 to 5 days 
(5 half-lives) PLUS 30 days after last dose. 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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TAK-954
Study No. TAK-954-2003
Page 80 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Appendix D
Investigator Consent to 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.
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 drug.

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-954-2003
Page 81 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Appendix E
Hepatic Function Categories Based on Child-Pugh Score
Classification of clinical severity:
Mild (Class A): total score 5-6 points.
Moderate (Class B): total score 7-9 points.
Severe (Class C): total score 10-15 points.
Assessment Parameters
Points Scored for Observed Findings
1 point
2 points
3 points
Encephalopathy grade (a)
none
1 or 2
3 or 4
Ascites
absence
slight
moderate
Serum bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
INR
<1.7
1.7-2.3
>2.3
Source: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf.
(a) Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) waves.
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
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TAK-954
Study No. TAK-954-2003
Page 82 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Appendix F
Detailed Descriptions of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 05 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Revised number of subjects based on the findings of the interim analysis.
The primary change occurs in Section 2.0 STUDY SUMMARY.
Initial 
wording:
Number of Subjects:
48 (12 per group)
Amended 
or new 
wording:
Number of Subjects:
48Approximately 36 to 41 subjects (maximum of 12 per group).
Rationale for Change:
One dosing arm was dropped based on conclusions obtained from the unblinded executive 
committee who performed the interim analysis.
Section 2.0 STUDY SUMMARY also contains this change. 
Change 2: Decreased the number of active treatment arms.
The primary change occurs in Section 8.1.3 Dose and Regimen.
Initial 
wording:
The subjects will be randomized to 1 of 4 treatment arms: TAK-954 0.1, 0.3, or 
1 mg; or placebo and will receive TAK-954 or placebo as a 60-minutes infusion IV 
once a day for 3 days starting on Day 1. 
Amended 
or new 
wording:
The subjects will be randomized to 1 of 4 treatment arms: TAK-954 0.1, 0.3, or 
1 mg; or placebo and will receive TAK-954 or placebo as a 60-minutes infusion IV 
once a day for 3 days starting on Day 1. The number of active treatment arms 
decreased based upon the prespecified interim analysis. To maintain the 
blinding of the study team, the specific treatment arm is not identified. This 
change was not necessitated by safety findings.
Rationale for Change:
Based on conclusions obtained from the unblinded executive committee who performed the 
interim analysis.
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Study No. TAK-954-2003
Page 83 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design.

Section 9.1.16 Documentation of Randomization.

13.2 Interim Analysis and Criteria for Early Termination.

Table 13.a.
Change 3: Revised the type of vital sign procedures collected and clarified the timing in relation 
to pharmacokinetic (PK) blood draws.
The primary change occurs in Section 9.1.5 Vital Sign Procedure.
Initial 
wording:
Vital signs will include body temperature (oral measurement), respiratory rate, 
sitting/supine blood pressure (systolic and diastolic, resting more than 5 minutes), 
and pulse (beats per minute).
When vital signs are scheduled at the same time as blood draws, the blood draw will 
take priority and vital signs will be obtained within 0.5 hour before or after the 
scheduled blood draw.
Amended 
or new 
wording:
Vital signs will include body temperature (oral measurement), respiratory rate,
sitting/supine blood pressure (systolic and diastolic, resting more than 5 minutes), 
and pulse (beats per minute).
When vital signs are scheduled at the same time as PK blood draws, the PK blood 
draw will take priority and vital signs will be obtained within 0.5 hour before or after 
the scheduled blood draw.
Rationale for Change:
Decrease the number of procedures needed and clarify the timing in relation to PK blood draws.
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Study No. TAK-954-2003
Page 84 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Change 4: Elimination of optional PK samples.
The primary change occurs in Section 9.1.14.1 Collection of Plasma for PK Sampling.
Initial 
wording:
The subjects will have PK samples collected as follows:
Days 1: prior to dosing (0 hour), and at 0.5 (optional), 1 (end of infusion), 1.5 
(optional), 2, and 4 hours after start of infusion. 
Day 2: prior to dosing (0 hour), 0.5 (optional), 1 (end of infusion), 1.5 (optional), 2, 
5, 7, and 9 hours after the start of the infusion. 
Day 3: prior to dosing (0 hour), 0.5 (optional), 1 (end of infusion), 1.5 (optional), 2, 
and 4 (optional) hours after start of infusion.
Amended 
or new 
wording:
The subjects will have PK samples collected as follows:
Days 1: prior to dosing (0 hour), and at 0.5 (optional), 1 (end of infusion), 1.5 
(optional), 2, and 4 hours after start of infusion. 
Day 2: prior to dosing (0 hour), 0.5 (optional), 1 (end of infusion), 1.5 (optional), 2, 
5, 7, and 9 hours after the start of the infusion. 
Day 3: prior to dosing (0 hour), 0.5 (optional), 1 (end of infusion), 1.5 (optional), 
and 2, and 4 (optional) hours after start of infusion.
Rationale for Change:
To decrease the amount of blood needed from subjects.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY also contains this change.
Figure 6.a Schematic of Study Design.
Table 9.b. Primary Specimen Collections.
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Study No. TAK-954-2003
Page 85 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Change 5 Revised the timing of vital sign measurements.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
(d) Vital signs will be collected upon arrival and departure from the Clinical 
Research and Trials Unit, and at the time of the PK samples.
Amended 
or new 
wording:
(d) Vital signs will be collected at Screening and Baseline, and on Days 1, 2, 3, 
and 4 upon arrival and departure from the Clinical Research and Trials Unit, and at 
the time and on Days 1, 2, and 3 prior to dosing (0 hour), 1 (end of the PK sample
infusion), and 2 hours after start of infusion.
Rationale for Change:
Correction of vital sign measurement timing.
Change 6: Eliminated instruction of the timing of PK sampling and electrocardiogram
procedures.
The primary change occurs in Section 9.1.14.1 Collection of Plasma for PK Sampling.
Deleted 
text:
When a PK sample coincides with an ECG or vital signs measurement, the ECG will 
take priority over the vital signs measurement.
Rationale for Change:
As the drug is administered via IV infusion, it is important to have the PK sample obtained as 
soon as possible at the end of infusion in order to calculate the Cmax. Waiting for an ECG 
measurement will significantly increase the variability across subjects. There is no safety issue 
for doing it either way.
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TAK-954
Study No. TAK-954-2003
Page 86 of 86
Protocol Incorporating Amendment No. 05
19 December 2018
Change 7: Revised information related to interim analysis.
The primary change occurs in Section 13.2 Interim Analysis and Criteria for Early Termination.
Initial 
wording:
An interim analysis will be conducted when approximately half of the subjects have 
completed the study. Efficacy and safety data will be reviewed to determine if the 
study should be modified based on the interim analysis results. If needed, the 
changes will be related to dose selection, sample size modification, or study 
termination. 
An executive committee within Takeda composed of a senior clinician, a senior 
statistician, a senior clinical pharmacologist, and a senior pharmacovigilance 
scientist not involved in the study will review the interim analysis results and make 
recommendations for changes to the study, if appropriate. All members of the study 
team and the investigative team will remain blinded to treatment arm assignment and 
treatment arm results until the completion of the study.
Amended 
or new 
wording:
An interim analysis will be was conducted when approximately half of the subjects 
have completed the study. Efficacy and safety data will be was reviewed to 
determine if the study should be modified based on the interim analysis results. If 
needed, the changes will be related to dose selection, sample size modification, or 
study termination. 
An executive committee within Takeda composed of a senior clinician, a senior 
statistician, a senior clinical pharmacologist, and a senior pharmacovigilance 
scientist not involved in the study will have review reviewed the interim analysis 
results and make made recommendations for changes to the study, if appropriate. 
All members of the study team and the investigative team will remain blinded to 
treatment arm assignment and treatment arm results until the completion of the 
study.
Based upon the results of the preplanned interim analysis, 1 of the TAK-954 
doses was dropped. The specific dose dropped is not specified in order to 
maintain the blind of the study team. The sample size for the remaining 
treatment arms will not change.
Rationale for Change:
Based on conclusions obtained from the unblinded executive committee who performed the 
interim analysis.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6809fbaa4
Amendment 05 to A Dose-Ranging, Randomized, Parallel, Placebo-Controlled Study to Assess the Effect of
TAK-954 on Gastrointestinal and Colonic Transit in Patients with Diabetic or Idiopathic Gastroparesis
Clinical Science Approval
20-Dec-2018 14:59 UTC
Statistical Approval
20-Dec-2018 15:28 UTC
Pharmacovigilance Approval
20-Dec-2018 15:30 UTC
Clinical Pharmacology Approval
20-Dec-2018 18:55 UTC
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PPD

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1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-954-2003
A Dose-Ranging, Randomized, Parallel, Placebo-Controlled Study to Assess the Effect of 
TAK-954 on Gastrointestinal and Colonic Transit in Patients with Diabetic or Idiopathic
Gastroparesis
PHASE 2a
Version: 1.0 
Date: 25 September 2018
Prepared by:
Based on:
Protocol Version: <Amendment 4>
Protocol Date: <11 September 2018>
PPD
Property of Taked
l
da: For non
ersision: <
on
ercial use only and subject to the applicable Terms of Use
dy to Ass
to A
y
with Dia
with D
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Statistical Analysis Plan Final v1.0 
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Statistical Analysis Plan Final v1.0 
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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
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoint.......................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Safety Endpoints........................................................................................................9
5.4
Exploratory Endpoints ...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Definition of Study Days and Study Visit Windows...........................................11
7.1.2
Missing Data......................................................................................................14
7.2
Analysis Sets ...........................................................................................................15
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................16
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Endpoint(s).............................................................................16
7.8.2
Secondary Efficacy Endpoint(s).........................................................................16
7.8.3
Additional Efficacy Endpoint(s).........................................................................16
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................17
7.9.1
Pharmacokinetic Analysis ..................................................................................17
7.9.2
Pharmacodynamic Analysis ...............................................................................17
7.9.2.1 Primary PD endpoint....................................................................................17
7.9.2.2 Secondary PD endpoint ................................................................................18
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7.10
Other Outcomes.......................................................................................................18
7.11
Safety Analysis........................................................................................................19
7.11.1 Adverse Events ..................................................................................................19
7.11.2 Clinical Laboratory Evaluations .........................................................................19
7.11.3 Vital Signs .........................................................................................................20
7.11.4 12-Lead ECGs ...................................................................................................20
7.11.5 Other Observations Related to Safety.................................................................21
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................22
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Detectable Effect Sizes for PD Endpoints.......................................10
LIST OF IN-TEXT FIGURES
Figure 7.a
Schematic of study design..................................................................................12
LIST OF APPENDICES
Appendix A
Clinical Laboratory Tests and Screening ............................................................23
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs..............................26
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........27
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Statistical Analysis Plan Final v1.0 
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3.0
LIST OF ABBREVIATIONS
5HT4 
serotonin
99mTc
technetium-99m
111In 
indium chloride isotope
AC 
ascending
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC 
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC24,ss 
area under the concentration-time curve from time 0 to time 24, at steady state
AUCτ 
area under the concentration-time curve during a dosing interval
AV 
atrioventricular
BP 
blood pressure
BMI 
body mass index
BUN
blood urea nitrogen
%CV 
percent coefficient of variation
Cmax 
maximum observed concentration
Cmax,ss
maximum observed concentration during a dosing interval, at steady state
Ctrough 
observed concentration at the end of a dosing interval
CPK
creatine phosphokinase
CRF
case report form
CYP
cytochrome P450
DC
Descending colon
eCRF 
electronic case report form
ECG
electrocardiogram
EFI 
enteral feeding intolerance
FAS 
full analysis set
FDA
Food and Drug Administration
FSH 
follicle-stimulating hormone
GC
geometric center
GCP 
Good Clinical Practice
GCSI 
Gastroparesis Cardinal Symptom Index
GGT 
γ-glutamyl transferase
GI 
gastrointestinal
HbA1c 
glycosylated hemoglobin
HIV
human immunodeficiency virus
hCG 
human chorionic gonadotropin
CCI
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Statistical Analysis Plan Final v1.0 
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HR 
heart rate
ICH 
International Conference on Harmonisation
ICU 
intensive care unit
INR
international normalized ratio
IRB 
institutional review board
IUD 
intrauterine device
IV 
intravenous
IVRS
Interactive Voice Response System
kcal 
kilocalorie
LFT(s) 
liver function test(s)
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MTD 
maximum tolerated dose
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL 
no-observed-adverse-effect level
NOEL 
no-observed-effect-level
PD
pharmacodynamics
PGx 
pharmacogenomic(s)
PK
pharmacokinetics
PPS 
per protocol set
PRO
patient-reported outcome
PTE
Pretreatment event
QD
Once daily
QOL
quality-of-life
QTc 
corrected QT interval
QTcF 
QT interval with Fridericia correction method
RS 
rectosigmoid colon
SAE
serious adverse event
SAP
statistical analysis plan
SDB
standard database
SUSARs 
suspected unexpected serious adverse reactions
SVT 
supraventricular tachycardia
T1/2 
half-emptying time
TC 
transverse colon
TLGs
tables, listings, and graphs
ULN
upper limit of normal
VT
Ventricular tachycardia
WHODrug
World Health Organization Drug Dictionary
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TAK-954-2003
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Statistical Analysis Plan Final v1.0 
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4.0
OBJECTIVES
4.1
Primary Objectives
To evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in 
subjects with diabetic or idiopathic gastroparesis assessed by scintigraphy.
4.2
Secondary Objectives
!
To evaluate the PD effects of TAK-954 on intestinal and colonic transit time assessed by 
scintigraphy.
!
To evaluate the PK of TAK-954 in subjects with gastroparesis.
!
To assess the safety and tolerability of multiple doses of TAK-954.
4.3
Additional Objectives
4.4
Study Design
This is a phase 2a dose-ranging, randomized, parallel group, double-blind, placebo-controlled 
study evaluating the effects of TAK-954 on gastric, small bowel, and colonic transit in diabetic 
subjects reporting symptoms of gastroparesis with previously documented delay in stomach 
emptying or in subjects with diagnosis of idiopathic gastroparesis. Twelve subjects per treatment 
group will be evaluated.
This study consists of 3 periods and a Follow-up: a Screening Period, a Baseline Period (between 
Day -14 and Day -6), a Treatment Period (Days 1 to 4), and a Follow-up Phone Call (Days 10 to 
14). Women of childbearing potential will receive an additional Follow-up Phone Call 
(Days 38-43).
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Statistical Analysis Plan Final v1.0 
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Subjects will have an initial Screening Visit, then will undergo a baseline gastric emptying 
assessment with scintigraphy scans acquired at 0, 1, 2, 3, and 4 hours after radiolabeled meal, 
between Day -14 and Day -6 (Baseline Visit). At least 48 hours prior to baseline scintigraphy, 
female subjects must have a negative urine pregnancy test.
If eligibility criteria are fulfilled, subjects will be randomized on Day 1 to 1 of 4 treatment arms: 
TAK-954 0.1, 0.3, or 1 mg, or placebo. Subjects will receive TAK-954 or placebo as a 60-minute 
intravenous (IV) infusion (at any time in the morning prior to 12:00) once a day (QD) for 3 days 
starting on Day 1. Following the TAK-954 infusion on Day 2, subjects will undergo 
scintigraphic assessment of gastric, small bowel, and colonic transit of solids during the 
Treatment Period.
The subjects will have pharmacokinetic (PK) samples collected as follows:

Day 1: prior to dosing (0 hour) and at 0.5, 1 (end of infusion), 1.5, 2, and 4 hours after start 
of infusion.

Day 2: prior to dosing (0 hour,), 0.5, 1 (end of infusion), 1.5, 2, 5, 7, and 9 hours after the 
start of the infusion.

Day 3: prior to dosing (0 hour), 0.5, 1 (end of infusion), 1.5, and 2 hours after start of 
infusion, with an optional 4-hour sample.

Day 4: 25 hours after the start of the infusion on Day 3 (48 hours after the administration of 
the radiolabeled meal on Day 2, same time as the 48-hour geometric center measurement).
During the study, subjects will complete a daily diary to record their bowel habits and as well as 
their global score using the GCSI. The On-Study Bowel Habit Diary Card will be dispensed at 
Screening to be completed daily from Screening and through the Treatment Period. The 
completed Bowel Habit Diary Card will be collected at the conclusion of the study.
All participating subjects will have a 6-hour Holter monitor placed at the Baseline Visit. On 
Day 1, subjects will have continuous ECG monitoring for up to 4 hours after the infusion, then 
continuous monitoring with a Holter monitor which will be placed prior to the first dose on 
Day 1 until the morning of Day 3.
Participants will undergo follow-up safety monitoring by phone 7-10 days post last treatment 
dose. The study will be considered completed after the last subject’s Follow-up Phone Call.
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Statistical Analysis Plan Final v1.0 
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
!
The primary endpoint for this study is half-emptying time (T1/2) of gastric emptying of 
solids.
5.2
Secondary Endpoints
!
Colonic geometric center at 4, 24, and 48 hours after the radiolabeled meal.
!
Colonic filling at 6 hours (measure of small bowel transit time) after the radiolabeled meal.
!
T1/2 of ascending colon emptying.
!
The following PK parameters of TAK-954:
–
Area under the concentration-time curve during a dosing interval (AUCτ), Cmax, and 
observed concentration at the end of a dosing interval (Ctrough).
5.3
Safety Endpoints
!
The percentage of subjects who experience at least 1 treatment-emergent adverse event.
!
The percentage of subjects who discontinue due to an AE.
!
The incidence of subjects who meet the markedly abnormal criteria for safety laboratory tests 
postdose.
!
The incidence of subjects who meet the markedly abnormal criteria for vital sign 
measurements postdose. 
!
The percentage of subjects who meet the markedly abnormal criteria for safety 12-lead ECG 
parameters and Holter monitor postdose.
5.4
Exploratory Endpoints
PPD
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TAK-954-2003
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Statistical Analysis Plan Final v1.0 
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6.0
DETERMINATION OF SAMPLE SIZE
Table 6.a below summarizes data for the primary response measures and uses the percent 
coefficient of variation, (%CV) to estimate the effect size detectable with 80% power based on a 
2 sample z-test (ie, assuming the variation values are known) at a 2-sided alpha level of 0.05. 
The effect size is the difference in group means as a percentage of the overall mean for each 
response and assumes 12 subjects per group. Based on data acquired using the same methods in 
the laboratory, the sample size of 12 subjects per group provides 80% power to detect 
approximately 30% changes in the primary endpoints of the study: gastric emptying, and overall 
colonic transit. This magnitude of change is considered clinically significant. The ANCOVA 
should provide 80% power to detect similar (pairwise) differences using a pooled estimate of 
variation across all 3 groups and potentially even smaller effect sizes by adjusting for important 
covariates. The data from the scintigraphic transit studies are unpublished but based on the same 
methods proposed for this study.
Table 6.a
Summary of Detectable Effect Sizes for PD Endpoints
Assuming n=12/Group in Each of the 4 Dose Groups
Response Type
Mean
SD
%CV
Effect Size (%) †
Gastric emptying of solids T1/2 min (n=319)
122
29.8
24.5
34.2
Colonic filling at 6 h, % (n=63)
44
29
66
79
GC at 24 h (n=220)
2.4
0/9
36
52
Ascending colon T1/2 h (n=50)
15.0
8.0
53
63
† Detectable with 80% power, α=0.05.
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Statistical Analysis Plan Final v1.0 
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Statistical analysis will be performed using the SAS System, Version 9.4.
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. 
7.1.1
Definition of Study Days and Study Visit Windows
Study Day 1 is defined as the date of the first dose of study drug. 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]. 
Unless specified otherwise, for all PD, symptom assessment, and safety endpoints, baseline is 
defined as the last non-missing measurement prior to the first dose of study drug.
Scintigraphy will be performed at 0, 1, 2, 3, and 4 hours post-radiolabeled meal on baseline visit 
(Days -14 to Day -6); on Day 2 at every 0.5 hour for first 4 hours post radiolabeled meal, then 
hourly until 9 hours post start of infusion; on Day 3 at 1 hour post start of infusion; and on Day 4 
at 25 hours post start of infusion on Day 3.
PK timepoints will be collected on Day 1 prior to dosing (0 hour) and at 0.5, 1, 1.5, 2, and 4 
hours after start of infusion; on Day 2 prior to dosing (0 hour,), 0.5, 1, 1.5, 2, 5, 7, and 9 hours 
after the start of the infusion; on Day 3 prior to dosing (0 hour), 0.5, 1, 1.5, and 2 hours after start 
of infusion, with an optional 4-hour sample; and on Day 4 at 25 hours post start of infusion on 
Day 3.
Vital signs will be collected upon arrival and departure from the Clinical Research and Trials 
Unit and at the time of the PK. Physical examination will be conducted prior to dosing on 
Days 1, 2, and 3. 12-lead ECG will be performed prior to each IV infusion, within 30 minutes 
post infusion, and at discharge on Days 1, 2, and 3; and at the Final Visit on Day 4 or Early 
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Statistical Analysis Plan Final v1.0 
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Termination Visit. In addition, a 12-lead ECG will be performed when needed, if a subject 
develops symptoms suggestive of cardiovascular origin (eg, dizziness, chest pain).
A schematic of the study design is included as Figure 7.a.
Figure 7.a
Schematic of study design
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Statistical Analysis Plan Final v1.0 
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Statistical Analysis Plan Final v1.0 
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7.1.2
Missing Data
There will be no imputation of incomplete or missing data unless otherwise indicated. 
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Statistical Analysis Plan Final v1.0 
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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
The Full Analysis Set (FAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects in this set will be analyzed according to the treatment they were randomized 
to receive.
The per protocol set (PPS) analysis set is a subset of the FAS. The PPS consists of all subjects 
who do not violate the terms of the protocol in a way that would significantly impact the efficacy 
assessment. All decisions to exclude subjects from the PPS dataset will be made prior to the 
unblinding of the study and subject to clinical review. This analysis set will be for efficacy 
analyses only and can be considered as a sensitivity analysis in support of the primary analysis 
based on the FAS.
The Safety Analysis Set (SAF) will include all subjects who receive at least 1 dose of study drug. 
Subjects in this set will be analyzed according to the treatment that was actually received.
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
The PK Analysis Set is defined as all subjects who receive at least 1 dose of study drug and have 
sufficient blood sampling to allow for PK evaluation.
7.3
Disposition of Subjects
A subject disposition summary will be provided. Subjects’ study completion data, including 
reasons for premature termination, will be provided in listings and also summarized.
Significant protocol deviations will be summarized.
A summary of screening failures will also be provided.
7.4
Demographic and Other Baseline Characteristics
For continuous variables (age, weight, height, and body mass index [BMI]), summary statistics 
will be generated. BMI (in kg/m2) will be calculated using the subject’s baseline height and 
weight measurements and summarized.
For categorical variables, the number and percentage of subjects in each category will be 
presented.
There will be no inferential analysis of demographic and baseline characteristics.
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.
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Statistical Analysis Plan Final v1.0 
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Medical history and concurrent medical conditions will be coded using the latest version of 
MedDRA, and will be summarized by treatment and overall using System Organ Class (SOC)
and MedDRA preferred term (PT). 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 listing.
7.6
Medication History and Concomitant Medications
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 48 hours 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 World Health 
Organization Drug Dictionary (WHODrug), and summarized by giving the number and 
percentage of subjects by preferred medication name 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 report 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.
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. No summary statistics for the extent of exposure to study drug or compliance 
calculations will be performed for this study.
7.8
Efficacy Analysis
7.8.1
Primary Efficacy Endpoint(s)
Not applicable
7.8.2
Secondary Efficacy Endpoint(s)
Not applicable
7.8.3
Additional Efficacy Endpoint(s)
Not applicable
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Statistical Analysis Plan Final v1.0 
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
PK parameters will be determined from the concentration-time data for all evaluable subjects 
using non-compartmental analysis. Actual sampling times, rather than scheduled sampling times, 
will be used in all PK computations involving sampling times for plasma PK parameters.
For TAK-954, the following PK parameters including, but not limited to, will be calculated as 
appropriate:

AUCτ: Area under the concentration-time curve during a dosing interval (Day 1 to 3).

Cmax: Maximum observed concentration (Day 1 to 3).

Cthrough: Observed concentration at the end of a dosing interval (Day 2 and 3).
The plasma concentration of TAK-954 will be summarized by treatment group over each 
scheduled sampling time point using descriptive statistics (N, arithmetic mean, SD, SE, CV%, 
median, minimum and maximum). In addition, the figures for mean plasma concentrations of 
TAK-954 versus time (linear and semi-log scale) will be generated, in overall population and by 
treatment group.
Additional plasma PK parameters may be calculated if necessary, in accordance with the Clinical
Pharmacology Analysis Plan (CPAP).
7.9.2
Pharmacodynamic Analysis
The analyses and summaries for PD will be based on the FAS.
7.9.2.1
Primary PD endpoint
The primary PD endpoint is the half-emptying time (T1/2) of gastric emptying of solids.
Geometric mean of counts in anterior and posterior gastric regions of interest will be used to 
estimate by power exponential analysis, the proportionate emptying over time of counts from 
99mTc solids and 111In from the stomach. Gastric emptying from the power exponential analysis 
for the post injection period will be calculated and compared for the different treatments. TheT1/2 
of gastric emptying of solids will be estimated by the linear interpolation using the slope of the 
2 data points before and after 50% has emptied from the stomach. If less than 50% empty at 
4 hours, the 3 data points at 180, 210, and 240 minutes will be used to project the time the T1/2
value.
Analysis of covariance (ANCOVA) methods will be used to assess the effect of treatment on the 
half-emptying time of gastric emptying of solids, including gastroparesis type (diabetic or 
idiopathic), age, gender, BMI, and the baseline measurement of gastric emptying T1/2 as 
covariates. Dunnett’s test will be used to compare each treatment arm to placebo. Multiplicity 
adjusted and unadjusted 95% 2-sided confidence intervals will be presented. Normality will be 
tested using the Shapiro Wilk W test with criteria <0.01. If normality is not achieved, a natural 
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Statistical Analysis Plan Final v1.0 
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log transformation may be done, and normality testing will be repeated. If normality is not 
achieved, a non-parametric test (such as Kruskal Wallis) may be use. 
7.9.2.2
Secondary PD endpoint
Colonic geometric center at 4, 24, and 48 hours post meal will be estimated using geometric 
mean of counts in ascending, transverse, descending and rectosigmoid colon and stool (weighted 
by factors of 1 to 5, respectively). The geometric center is the weighted average of counts in the 
different colonic regions: ascending (AC), transverse (TC), descending (DC), rectosigmoid (RS), 
and stool. At any time, the portion of colonic counts in each colonic region is multiplied by its 
weighting factors as follows:
(%AC x 1 + %TC x 2 + %DC x 3 + %RS x 4 + %stool x 5)/100 = geometric center
Thus, a high geometric center implies faster colonic transit. A geometric center of 1 implies that 
all isotope is in the ascending colon, and a geometric center of 5 implies that all isotope is in the 
stool.
Colonic filling at 6 hours post meal will be estimated by determining the amount of identified
99mTc -labeled solid meal within the colon at 6 hours with the value corrected for downscatter of 
radioactivity from the 111Indium chloride isotope located within the same area appearing within 
the technetium window of analysis.
T1/2 of ascending colon emptying will be estimated by power exponential analysis of the 
proportionate emptying over time of counts from the colon. The primary data for this analysis 
will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly 
scans on the first day of transit measurement and the 24 hour data. The T1/2 of ascending colon 
emptying is also estimated by plotting the activity-time curve for percent residing in the 
ascending colon; linear interpolation is used to connect points.
The effect of treatment on the secondary endpoints will also be assessed using an ANCOVA 
model. The covariates considered for inclusion in the analyses will be gastroparesis type 
(diabetic or idiopathic), age, gender, BMI, and the baseline measurement of the respective 
endpoint. Dunnett’s test will be used to compare each treatment arm to placebo. Multiplicity 
adjusted and unadjusted 95% 2-sided confidence intervals will be presented. Normality will be 
tested using the Shapiro Wilk W test with criteria <0.01. If normality is not achieved, a natural 
log transformation may be done, and normality testing will be repeated. If normality is not 
achieved, a non-parametric test (such as Kruskal Wallis) may be use. 
7.10
Other Outcomes
Patient Reported Outcomes:
Information on the global score using the GCSI, as well as bowel movement frequency per day 
and average stool consistency on the Bristol stool form scale, will be tabulated by each day. 
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Statistical Analysis Plan Final v1.0 
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7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign 
parameters, 12-lead electrocardiogram (ECG) results.
All summaries of safety data are based on subjects in the Safety Set.
7.11.1 Adverse Events
All AE verbatim terms will be coded by SOC and PT using the latest version of MedDRA 
dictionary. 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).
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). 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.

Treatment-emergent SAEs by SOC and PT.
An AE of Special Interest (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication 
by the investigator to Takeda may be appropriate.
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include hematology, serum chemistries, and urinalysis tests. Refer 
to Appendix A for the list of all clinical laboratory tests.
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Statistical Analysis Plan Final v1.0 
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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 measurement. Only the scheduled measurements 
will be included in the summary. No inferential analysis will be performed.
Individual results for hematology laboratory tests and serum chemistry tests will be evaluated 
against the Takeda predefined laboratory markedly abnormal value (MAV) criteria 
(Appendix B). 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 values 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 and conventional units in the data 
listings. Laboratory data outside of the normal reference range will be flagged on the listing 
along with values meeting MAV criteria.
7.11.3 Vital Signs
Vital sign measurements include body temperature, heart rate, respiratory rate, and blood 
pressure. 
Descriptive statistics (N, mean, median, SD, minimum and maximum) of vital signs parameters 
will be summarized for baseline, postbaseline, and change from baseline at each scheduled time 
point. Only the vital signs 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 C) 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.
7.11.4 12-Lead ECGs  
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.
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Statistical Analysis Plan Final v1.0 
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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 D) 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 and Holter monitor data will be presented in the listings. ECG MAVs will be flagged in 
the listings.
7.11.5 Other Observations Related to Safety
Not applicable
7.12
Interim Analysis
An interim analysis will be conducted when approximately half of the subjects have completed
the study. Efficacy and safety data will be reviewed to determine if the study should be modified
based on the interim analysis results. If needed, the changes will be related to dose selection,
sample size modification, or study termination.
7.13
Changes in the Statistical Analysis Plan 
None.
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Statistical Analysis Plan Final v1.0 
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8.0
REFERENCES
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Appendix A
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.
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Statistical Analysis Plan Final v1.0 
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Appendix B
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
<100 x 103/L
>450 x 103/L
SI
<7100x 109/L
>450 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
--
>ULN - 2.5 x ULN if baseline was 
normal; 2.0 - 2.5 x baseline if 
baseline was abnormal
Alkaline phosphatase
Both
--
>ULN - 2.5 x ULN if baseline was 
normal; 2.0 - 2.5 x baseline if 
baseline was abnormal
Total bilirubin
Conventional
--
>ULN - 1.5 x ULN if baseline was 
normal; > 1.0 - 1.5 x baseline if 
baseline was abnormal
SI
--
>ULN - 1.5 x ULN if baseline was 
normal; > 1.0 - 1.5 x baseline if 
baseline was abnormal
Albumin
Conventional 
<3 g/dL
--
SI 
<30 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
>5.5 mEq/L
SI
<3.0 mmol/L
>5.5 mmol/L
Glucose
Conventional
<55 mg/dL
>180 mg/dL
SI
<3 mmol/L
>10 mmol/L*
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
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Statistical Analysis Plan Final v1.0 
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Parameter
Unit 
Low Abnormal
High Abnormal
Calcium (corrected)
Conventional 
Corrected serum calcium 
of <LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; 
Ionized calcium <LLN -
1.0 mmol/L
Corrected serum calcium of >ULN 
- 11.5 mg/dL; >ULN - 2.9 mmol/L; 
Ionized calcium >ULN - 1.5 
mmol/L
SI
Corrected serum calcium 
of <LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; 
Ionized calcium <LLN -
1.0 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.

Unless for patients who have Diabetic at baseline.
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Statistical Analysis Plan Final v1.0 
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Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Heart Rate
bpm
<60 
>120
Systolic blood pressure
mm Hg
<90
>140 
Diastolic blood pressure
mm Hg
<60
>90
Body temperature
oC
oF
<35.6
<96.1
>37.7
>99.9
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Statistical Analysis Plan Final v1.0 
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Appendix D
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
QTcF Interval
≥500 milliseconds OR
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤60 milliseconds
≥120 milliseconds
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