Conditions: Postoperative Gastrointestinal Dysfunction
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 209
Healthy volunteers: no

Brief summary:
The main aim of this study is to check for side effects from TAK-954 and whether it speeds up the recovery of gastrointestinal function after small-bowel or large-bowel resection surgery.

Participants will be treated with TAK-954 before surgery and up to 10 days after surgery.

Detailed description:
The drug being tested in this study is called TAK-954. In this study TAK-954 is being administered presurgery to evaluate if it can enhance the recovery of GI function postsurgery in participants undergoing open or laparoscopic-assisted partial small- or large-bowel resection. In addition, some participants will also receive TAK-954 postoperatively to evaluate if there is an additional benefit when this drug is administered both pre and post-surgery.

The study will enroll approximately 180 participants. Participants will be equally randomized into one of the three remaining parallel treatment arms- which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need).

All participants will be given intravenous infusion preoperation and daily postoperation until return of upper and lower GI function or for up to 10 days.

This multi-center trial will be conducted in the United States and Germany. The overall time to participate in this study is up to 100 days. Participants will be treated with the study drug for up to 10 days after surgery or until return of GI function post-surgery (whichever occurs first).

Arms:
arm 1: TAK-954 placebo-matching, 60-minute infusion, intravenously (IV), once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days. arm 2: TAK-954 0.1 milligrams per 100 milliliters (mg/100 mL), 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days. arm 3: TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days. arm 4: TAK-954 0.1 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function. arm 5: TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Interventions: intervention 1: TAK-954 Placebo intervention 2: TAK-954
Intervention descriptions: intervention 1: TAK-954 placebo-matching intravenous infusion. intervention 2: TAK-954 intravenous infusion.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT03827655 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose 
Ranging Study to Evaluate the Efficacy and Safety of 2 Dose 
Regimens of Intravenous TAK-954 for the Prophylaxis and 
Treatment of Postoperative Gastrointestinal Dysfunction in Patients 
Undergoing Large- and Small-Bowel Resection 
TAK-954-2004
Protocol Version and Date: 
Version 5.0: 25-March-2021 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Ranging Study to Evaluate the 
Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and 
Treatment of Postoperative Gastrointestinal Dysfunction in Patients Undergoing Large- and 
Small-Bowel Resection
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Study Number:
TAK-954-2004
IND Number:
140120
EudraCT Number:
2018-003318-42
Compound:
TAK-954
Date:
23 March 2021
Version/Amendment 
Number:
5
Amendment History:
Date
Amendment Number
Amendment Type
Region
23 March 2021
Amendment 5
Substantial
Global
09 July 2019
Amendment 4
Substantial
Global
13 May 2019
Amendment 3
Substantial
Local (Germany)
23 April 2019
Amendment 2
Nonsubstantial
Local (Belgium)
19 December 2018
Amendment 1
Not applicable
Global
15 October 2018
Initial protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Development Center Americas, Inc. (TDCA) 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
European Contact
Serious adverse event and 
pregnancy reporting
PRA PVS Clinical Operations:
Email: MHGSafety@prahs.com
Fax: +44 1792 525720
PRA PVS Clinical Operations:
Email: MHGSafety@prahs.com
Fax: +44 1792 525720
Medical Monitor
(medical advice on protocol and 
study drug)
Medical Director, Clinical Science
Medical Director, Clinical Science
Responsible Medical Officer 
(carries overall responsibility 
for the conduct of the study)
Medical Director, Clinical Science
Medical Director, Clinical Science
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CONFIDENTIAL
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 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/Province)
Location of Facility (Country)
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1.3
Protocol Amendment Summary of Changes
Protocol Amendment 5 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 5. 
The primary reason for this amendment is to maintain subject safety and study integrity and 
provide flexibility to study participants in the context of the global coronavirus disease 2019 
(COVID-19) pandemic as permitted by local regulations. Study modifications to mitigate the 
impact of COVID-19 include the addition of Exclusion Criterion 15 for subjects with known 
COVID-19 infection, the addition of flexibility in procedures and the expansion of the duration of 
the screening period (including potential screening of subjects on the day of surgery), the 
allowance for a follow-up visit 14 days after the last dose to be performed via a phone call, the 
inclusion of COVID-19 as a reason for subject discontinuation from the study, and the allowance 
of electronic signature on the informed consent form if approved by the site institutional review 
boards/ethics committees.
Protocol Amendment 5 includes the addition of inclusion and exclusion criteria related to the 
American Society of Anesthesiologists (ASA) physical status classification and severe 
comorbidities to not enroll subjects with high risk of surgery.
This amendment also provides additional information from the updated Investigator’s Brochure 
Edition 5 (13 April 2020) that clarified mean TAK-954 exposure, added completed TAK-954 
studies, and provided additional information concerning the benefit-risk profile (Section 4.3
Benefit-Risk Profile).
In addition, this amendment clarifies the inclusion/exclusion criteria, changes to study assessments, 
and clarifies or modifies study procedures: removal of glucose-dependent insulinotropic peptide 
(GIP) and DNA blood sampling; adjustment of the number of and collection time windows of 
pharmacokinetic (PK) samples; adjustment of timing and number of electrocardiogram (ECG) 
procedures; and defined time assessment windows for the Day 14 visit, ECG procedures, and 
biomarker sampling.
Notably, just before this amendment, the planned interim analysis (IA) was conducted in 
accordance with the protocol to allow the internal monitoring committee (IMC) to review the 
safety and efficacy data. The IMC recommended the discontinuation of 2 active treatment arms, 
and Amendment 5 does update some of the language around dosing arms to reflect that change. 
Additionally, a revised sample size is provided for the remaining 3 treatment arms based on 
blinded assessments that were conducted using efficacy assumptions of the original protocol 
before the IA to mitigate the statistical, clinical, and operational risks to this study due to 
COVID-19 pandemic (ie, not resulting from the IA and data monitoring committee review of IA).
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Administrative changes incorporated in this amendment include changing the sponsor from 
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment Summary of Changes...............................................................5
2.0
STUDY SUMMARY ....................................................................................................21
3.0
STUDY REFERENCE INFORMATION ......................................................................27
3.1
Study-Related Responsibilities.................................................................................27
3.2
Principal Investigator/Coordinating Investigator ......................................................27
3.3
List of Abbreviations ...............................................................................................28
3.4
Corporate Identification...........................................................................................29
4.0
INTRODUCTION.........................................................................................................30
4.1
Background .............................................................................................................30
4.2
Rationale for the Proposed Study.............................................................................31
4.3
Benefit-Risk Profile .................................................................................................33
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................34
5.1
Objectives................................................................................................................34
5.1.1
Primary Objective(s)........................................................................................34
5.1.2
Secondary Objectives ......................................................................................34
5.1.3
Exploratory Objectives ....................................................................................34
5.2
Endpoints.................................................................................................................35
5.2.1
Primary Endpoint.............................................................................................35
5.2.2
Secondary Endpoints .......................................................................................35
5.2.3
Safety Endpoints..............................................................................................35
5.2.4
Exploratory Endpoints .....................................................................................36
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................36
6.1
Study Design ...........................................................................................................36
6.2
Justification for Study Design, Dose, and Endpoints ................................................40
6.3
End of the Study ......................................................................................................41
6.4
Premature Termination or Suspension of Study or Study Site...................................42
6.4.1
Criteria for Premature Termination or Suspension of the Study........................42
6.4.2
Criteria for Premature Termination or Suspension of Study Sites.....................42
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...........................................................................42
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............42
7.1
Inclusion Criteria .....................................................................................................42
7.2
Exclusion Criteria ....................................................................................................43
7.3
Excluded Medications..............................................................................................44
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................45
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................46
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................46
8.1
Study Drug and Materials ........................................................................................46
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................46
8.1.1.1
TAK-954.................................................................................................46
8.1.1.2
Ancillary Materials..................................................................................47
8.1.2
Storage ............................................................................................................47
8.1.3
Dose and Regimen...........................................................................................47
8.1.4
Overdose .........................................................................................................48
8.2
Study Drug Assignment and Dispensing Procedures ................................................49
8.3
Randomization Code Creation and Storage..............................................................49
8.4
Study Drug Blind Maintenance................................................................................50
8.5
Unblinding Procedure..............................................................................................50
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................50
9.0
STUDY PLAN ..............................................................................................................52
9.1
Study Procedures.....................................................................................................52
9.1.1
Informed Consent Procedure............................................................................52
9.1.2
Demographics, Medical History, and Medication History Procedure................52
9.1.3
Physical Examination Procedure (Including Neurology Examination)..............52
9.1.4
Weight, Height, and BMI.................................................................................53
9.1.5
Vital Sign Procedure........................................................................................53
9.1.6
Primary Efficacy Measurement........................................................................53
9.1.7
Study Surgery..................................................................................................54
9.1.8
Clinical Assessments .......................................................................................54
9.1.9
Documentation of Concurrent Medical Procedures ..........................................55
9.1.10
Documentation of Concomitant Medications ...................................................55
9.1.11
Documentation of Core ERP............................................................................55
9.1.12
Procedures for Clinical Laboratory Samples ....................................................55
9.1.13
Contraception and Pregnancy Avoidance Procedure ........................................56
9.1.14
Pregnancy........................................................................................................57
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9.1.15
ECG Procedure................................................................................................58
9.1.16
Biomarker Sample Collection ..........................................................................59
9.1.17
PK Sample Collection......................................................................................59
9.1.17.1
Collection of Plasma for PK Sampling.....................................................59
9.1.18
Primary Specimen Collection...........................................................................60
9.1.19
Documentation of Screen Failure.....................................................................60
9.1.20
Documentation of Randomization....................................................................60
9.1.21
Quality of Life Assessment..............................................................................61
9.2
Schedule of Observations and Procedures................................................................61
9.2.1
Post Study Care ...............................................................................................61
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................61
10.1
Definitions...............................................................................................................61
10.1.1
Pretreatment SAEs...........................................................................................61
10.1.2
AEs .................................................................................................................61
10.1.3
Additional Points to Consider for AEs .............................................................61
10.1.4
SAEs ...............................................................................................................63
10.1.5
Severity of AEs................................................................................................64
10.1.6
Management of Specific AEs...........................................................................64
10.1.6.1
CV Disorders...........................................................................................64
10.1.6.2
Serotonin Syndrome ................................................................................66
10.1.6.3
Diarrhea...................................................................................................67
10.1.6.4
Abnormal Liver Tests..............................................................................67
10.1.6.5
AESI .......................................................................................................67
10.1.7
Causality of AEs..............................................................................................68
10.1.8
Relationship to Study Procedures.....................................................................68
10.1.9
Start Date.........................................................................................................68
10.1.10 Stop Date.........................................................................................................68
10.1.11 Frequency........................................................................................................68
10.1.12 Action Concerning Study Drug........................................................................69
10.1.13 Outcome..........................................................................................................69
10.2
Procedures...............................................................................................................69
10.2.1
Collection and Reporting of AEs .....................................................................69
10.2.1.1
AE Collection Period...............................................................................69
10.2.1.2
AE Reporting...........................................................................................70
10.2.1.3
AESI .......................................................................................................70
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10.2.2
Collection and Reporting of SAEs ...................................................................70
10.3
Follow-up of SAEs ..................................................................................................71
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...71
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................71
11.1
Independent CEC.....................................................................................................71
11.2
Internal Monitoring Committee................................................................................72
12.0
DATA HANDLING AND RECORDKEEPING............................................................72
12.1
CRFs (Electronic and Paper)....................................................................................72
12.2
Record Retention .....................................................................................................73
13.0
STATISTICAL METHODS..........................................................................................73
13.1
Statistical and Analytical Plans ................................................................................73
13.1.1
Analysis Sets ...................................................................................................74
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................74
13.1.3
Efficacy Analysis.............................................................................................74
13.1.4
PK Analysis.....................................................................................................75
13.1.5
Safety Analysis................................................................................................75
13.2
IA and Criteria for Early Termination ......................................................................75
13.3
Determination of Sample Size..................................................................................76
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................76
14.1
Study-Site Monitoring Visits ...................................................................................76
14.2
Protocol Deviations..................................................................................................77
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................77
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................77
15.1
IRB and/or IEC Approval ........................................................................................77
15.2
Subject Information, Informed Consent, and Subject Authorization .........................78
15.3
Subject Confidentiality ............................................................................................79
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................80
15.4.1
Publication and Disclosure...............................................................................80
15.4.2
Clinical Trial Registration................................................................................80
15.4.3
Clinical Trial Results Disclosure......................................................................80
15.5
Insurance and Compensation for Injury....................................................................81
16.0
REFERENCES..............................................................................................................81
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LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen Prior to Protocol Amendment 5............................................48
Table 8.b
Dose and Regimen as a Result of Protocol Amendment 5...................................48
Table 9.a
Clinical Laboratory Tests...................................................................................56
Table 9.b
Primary Specimen Collection.............................................................................60
Table 10.a
NCI CTCAE ......................................................................................................64
Table 10.b
Management of QT Prolongation by NCI CTCAE Grade...................................65
Table 10.c
Management of SVT by NCI CTCAE Grade......................................................66
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design Prior to Protocol Amendment 5...............................38
Figure 6.b
Schematic of Study Design By Protocol Amendment 5......................................39
Figure 9.a
Numerical Rating Scale......................................................................................54
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................87
Appendix C
Elements of the Subject Informed Consent.........................................................89
Appendix D
Investigator Consent to Use of Personal Information..........................................92
Appendix E
Protocol History.................................................................................................93
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc. 
Compound:
TAK-954
Title of Protocol: A Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Dose Ranging Study to 
Evaluate the Efficacy and Safety of 2 Dose Regimens of 
Intravenous TAK-954 for the Prophylaxis and Treatment of 
Postoperative Gastrointestinal Dysfunction in Patients 
Undergoing Large- and Small-Bowel Resection
IND No.: 140120
EudraCT No.:
2018-003318-42
Study Number: 2004
Phase: 2b
Study Design:
This phase 2, randomized, placebo-controlled, parallel 5-group, double-blind study is designed to determine: (1) if 
TAK-954 decreases the duration of gastrointestinal (GI) dysfunction in patients undergoing major abdominal open or 
laparoscopic-assisted surgeries that involve significant bowel manipulation, (2) whether preoperative dosing alone or 
a preoperative and postoperative dosing regimen is the most effective dosing regimen to decrease the duration of 
postoperative GI dysfunction (POGD) and improve clinical outcomes, and (3) the most appropriate dose and dosing 
regimen to advance into phase 3.
Subjects will be randomized in a 1:1:1:1:1 ratio into 1 of 5 parallel treatment groups:

Regimen 1: Placebo (normal saline 100 mL infusion over 60 minutes) preoperation and daily postoperation until 
return of upper and lower GI function (ie, resolution of POGD) or for up to 10 days.

Regimen 2: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily postoperation until 
return of upper and lower GI function or for up to 10 days.

Regimen 3: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily postoperation until 
return of upper and lower GI function or for up to 10 days.

Regimen 4: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily placebo infusions 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily placebo infusions 
postoperation until return of upper and lower GI function or for up to 10 days.
Subject randomization will be stratified by laparoscopic and open surgery procedures.
Following an interim analysis (IA) specified in Protocol Amendment 4, 2 of the above TAK-954 regimens are 
discontinued based on internal monitoring committee (IMC) recommendations. As a result, eligible subjects will be 
equally randomized to into 1 of 3 the remaining parallel treatment groups:

Regimen 1: Placebo (normal saline 100 mL infusion over 60 minutes) preoperation and daily postoperation until 
return of upper and lower GI function (ie, resolution of POGD) or for up to 10 days.

Regimen 3: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily postoperation until 
return of upper and lower GI function or for up to 10 days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily placebo infusions 
postoperation until return of upper and lower GI function or for up to 10 days.
It is standard of practice for the postoperative care of patients after colorectal surgery to implement an enhanced 
recovery pathway (ERP) to reduce the time to recovery of GI function (motility). To provide a consistent ERP as 
baseline therapy for all subjects, they will receive the same core features of an ERP for postoperative care as outlined 
below:
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Core ERPs:

Minimize opioid use while maintaining adequate pain control through use of multimodal analgesia. Suggested 
analgesics include opioid alternatives such as nonsteroidal anti-inflammatory drugs (eg, ketorolac tromethamine 
IV), acetaminophen (paracetamol), or oral pregabalin when possible. It is recommended that at least 2 different 
analgesics with different mechanism of action are tried and failed before prescribing opioids. 

Maintenance of euvolemia and normal salt and electrolyte state in perioperative period.

No routine use of prophylactic nasogastric (NG) tubes postsurgery. NG tubes should only be used if there is a 
documented medical reason to justify them.

Use of a standardized risk-based strategy for postoperative nausea and vomiting (PONV) prophylaxis: use of 
preoperative antiemetic prophylaxis in patients with 1 or more risk factors of the simplified Apfel Score (female 
gender, planned postoperative use of opioids, nonsmokers, history of PONV/motion sickness).

Early oral feeding postsurgery when possible. Clear liquids after the surgery on Day 1, advancing to soft diet on 
Day 2 if tolerant to liquids (no nausea or vomiting). 

Early mobilization starting after the surgery on Day 1 when possible.
Criteria for resolution of upper and lower GI function is time to first tolerance of solid food (defined as no vomiting or 
no clinically significant nausea for 1 calendar day after a solid meal) and time to first spontaneous bowel movement, 
whichever occurs later, up to Day 10 postsurgery. 
Following hospital discharge, subjects will be instructed to contact their physician if they have recurring symptoms 
suggestive of POGD to evaluate the need for hospital readmission in case of relapse. All subjects will return to clinic 
for a follow-up visit 14 days (±4 days) post last dose; however, during the coronavirus disease 2019 (COVID-19) 
public health emergency, the follow-up visit 14 days post last dose may be conducted via phone call (eg, collection of 
AEs, concomitant medications, and monitoring) to extend flexibility to study subjects. In the case of a phone call 
follow-up, physical examination (including neurology examination), vital signs, or pregnancy test would not be 
collected; however, AEs will be assessed, including a safety check on any emerging clinical signs or symptoms. 
Subjects may be requested to return to the site for further safety assessment due to reported AEs at the investigator’s 
discretion. The type of visit (whether clinic visit or phone call) must be recorded in the study records. Quality of life 
assessments will be completed by the subject in their home on the same day as the safety follow-up call and completed 
questionnaires will be mailed to the clinic. Subjects will be contacted by phone 30 (±3 days) and 90 days (±7 days) 
posttreatment for a safety follow-up.
Two preplanned IAs will be conducted when a priori enrollment goals have been achieved. Bayesian approach will be 
applied after these IAs for decision making for potential study modification including futility, dose and dosing 
regimen decision, and sample size adjustment. In case dose modification is needed after the IA, the maximal dose for 
potential modification of doses/regimens will be 1.0 mg. The duration of drug administration (up to 10 days 
postsurgery) will not be changed. By this protocol amendment, the second IA is removed from the protocol.
Primary Objectives:
To assess the efficacy and safety of intravenous (IV) TAK-954 for accelerating the recovery of GI function 
postsurgery in patients undergoing open or laparoscopic-assisted partial small- or large-bowel resection.
Secondary Objectives:

To determine efficacy and safety of preoperative dosing of IV TAK-954 relative to preoperative and 
postoperative regimens of up to 10 days of IV TAK-954 for accelerating the recovery of GI function postsurgery.

To determine the relative efficacy and safety of 0.1 mg and 0.5 mg IV TAK-954 given either preoperatively alone 
or preoperatively and postoperatively compared with placebo of up to 10 days or resolution of GI dysfunction 
postsurgery for accelerating the recovery of GI function postsurgery. 

To determine the pharmacokinetics (PK) of TAK-954 in patients undergoing major abdominal surgery.
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Subject Population: Patients undergoing elective open or laparoscopic-assisted partial small— or large—bowel 
resection.
Number of Subjects:
The planned total sample size prior to Protocol Amendment 
5 is approximately 200 to 375 subjects:

TAK-954 0.1 mg/100 mL preoperative and daily: 
minimum of 25 and up to a maximum of 100 subjects.

TAK-954 0.1 mg/100 mL preoperative only: minimum 
of 25 and up to a maximum of 100 subjects.

TAK-954 0.5 mg/100 mL preoperative and daily: 
minimum of 25 and up to a maximum of 100 subjects.

TAK-954 0.5 mg/100 mL preoperative only: minimum 
of 25 and up to a maximum of 100 subjects.

Placebo: 100 subjects preoperatively and daily.
With this Protocol Amendment 5, the planned total sample 
size is approximately 180 subjects:
Enroll additional subjects to reach overall total of 
50 subjects/remaining treatment groups (actually 
accumulated sample size at IA plus the number of 
additional subjects to be enrolled after the IA) for the study: 

TAK-954 0.5 mg/100 mL preoperative and daily: 
minimum overall total of approximately 50 subjects.

TAK-954 0.5 mg/100 mL preoperative only: minimum 
overall total of approximately 50 subjects.

Placebo: overall total of approximately 50 subjects 
preoperatively and daily.
Number of Sites: 
Estimated total: approximately 30 in North America 
and Europe. 
Dose Levels:
Prior to Protocol Amendment 5: TAK-954 0.1 and 0.5 mg
Placebo
By Protocol Amendment 5: TAK-954 0.5 mg
Placebo
Route of Administration:
TAK-954 IV
Placebo IV
Duration of Treatment:
Resolution of postoperative GI function or 10 days.
Period of Evaluation:
Up to 10-day treatment period; 14-day observation 
period post last dose for recurrence of symptoms 
(inpatient or outpatient); safety follow-up 
14 (±4 days), 30 (±3 days), and 90 days (±7 days) post 
last dose.
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Main Criteria for Inclusion:
Subject eligibility is determined according to the following criteria before entry into the study:

The subject is male or female (and not pregnant) and is at least 18 years old.

The subject is scheduled to undergo a laparoscopic-assisted, or open partial small- or large-bowel, resection.

The subject’s American Society of Anesthesiologists (ASA) physical status classification is ASA 1 to 3.

A female subject of childbearing potential willing and agreeable to use highly effective contraception or sexual 
abstinence during the course of the study and up to 30-days posttreatment.
Main Criteria for Exclusion:
Any subject who meets any of the following criteria will not qualify for entry into the study:

Has significant mechanical bowel obstruction that is not expected to resolve after the surgery, short bowel 
syndrome, pre-existing clinically significant GI motility disorder (eg, gastroparesis, scleroderma, chronic 
intestinal pseudo-obstruction), uncontrolled diabetes (glycosylated hemoglobin [HbA1c] >10%), has an active 
gastric pacemaker, or requires parenteral nutrition.

Previous major abdominal surgery (eg, gastrectomy, gastric bypass, gastric sleeve, lap banding, Whipple, 
pancreatic resection, total/subtotal colectomy, hemicolectomy, extensive bowel resection). 

History of radiation therapy to the abdomen or pelvis.

Scheduled to undergo any of the following surgeries: low anterior resection, total or subtotal colectomy, 
colostomy, ileostomy, or reversal of stoma, or has a diagnosis that requires rectal resection (eg, tumors in the 
anorectum) and will likely require lower anterior resection surgery. Subjects with planned surgery for which there 
is no anticipated significant rectal resection and is, therefore, likely to preserve anorectal function and continence 
postsurgery, will likely be eligible for inclusion in the study if they meet all the study inclusion/exclusion criteria 
(eg, subjects with lesions not involving the rectum [sigmoid colon and above]).

Has pre-existing hepatic disease that meets Child-Pugh Class B (moderate; total score 7 to 9 points) or C (severe; 
total score 10 to 15 points).

Has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3 × upper limit of normal 
(ULN), or total bilirubin >2 × ULN.

Has an estimated glomerular filtration rate <30 mL/min.

Has received alvimopan, erythromycin, prucalopride, metoclopramide, domperidone, cisapride, mosapride, 
renzapride, or azithromycin in the 24 hours prior to starting study drug.

Has a resting heart rate of <50 beats per minute (bpm).

Has clinically significant electrocardiogram (ECG) abnormalities indicative of cardiac conduction abnormality or 
acute cardiac instability as determined by the investigator at screening; more than first degree atrioventricular 
(AV) block; >5 beats of nonsustained ventricular tachycardia (VT) at a rate >120 bpm; or ECG changes 
consistent with acute myocardial ischemia or infarction. 

Has a QT interval with Fridericia correction method (QTcF) interval ≥450 msec or other factors that increase the 
risk of QT prolongation or arrhythmic events at screening. The records of subjects with bundle branch block and 
a prolonged QTcF should be reviewed by a medically qualified person in consultation with the medical monitor 
and the sponsor for potential inclusion.

Had acute myocardial infarction or ischemia within the past 12 months. Subjects with increased cardiac risks for 
surgery including coronary artery disease or prior myocardial infarction and evidence of reduced left ventricular 
function or history of angina should be assessed by the investigator for stability and control of their cardiac 
condition and risk of surgery, and excluded if in the investigator’s opinion, participation in the study is not 
considered appropriate. The sponsor should be consulted if subjects with these conditions are considered by the 
investigator to be acceptable.
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
Had pulmonary embolism, deep venous thrombosis, or mechanical ventilation for any medical condition within 
the past 12 months. Subjects with a history of multiple venous thrombosis or pulmonary embolic events, history 
of a hypercoagulable condition, history of severe exacerbation for chronic obstructive pulmonary disease or 
evidence of pulmonary hypertension should be assessed by the investigator for stability and control of their 
conditions and risk of surgery, and excluded if in the investigator’s opinion, participation in the study is not 
considered appropriate. The sponsor should be consulted if subjects with these conditions are considered by the 
investigator to be acceptable.

Scheduled for abdominal surgery that is classified as emergency.
Main Criteria for Evaluation and Analyses:
The primary efficacy endpoint for this study is time from the end of surgery to resolution of upper and lower GI 
function (ie, time to tolerance of solid food [defined as first occurrence of no vomiting or no clinically significant 
nausea for 1 calendar day after a solid meal] and time to first spontaneous bowel movement, whichever occurs later) 
up to Day 10 postsurgery. 
Secondary endpoints for this study are:

Time from the end of the surgery (time the incision is closed) until ready for discharge (defined as the time until 
the subject presents effective intestinal transit [spontaneous bowel movement], tolerates solids without vomiting 
or clinically significant nausea for 1 calendar day after a solid meal, has satisfactory pain control with oral 
analgesics, and is medically stable/free of complications).

Time from the end of surgery until the discharge order is written.

Time from the end of the surgery to discharge from hospital.

Time from end of surgery to tolerance of solid food (defined as first occurrence of intake of solids without 
vomiting or clinically significant nausea for 1 calendar day after a solid meal) up to Day 10 postsurgery.

Time from end of surgery to first spontaneous bowel movement (defined as a stool not induced by the use of 
enemas or laxatives) up to Day 10 postsurgery.

Percent of subjects with POGD ≥5 days, defined as subjects unable to tolerate solid foods, take anything by 
mouth, or requiring insertion or reinsertion of NG at or after 5 days postsurgery.

Percentage of subjects requiring insertion of NG tube postsurgery, for drainage and symptom relief in case of 
persistent nausea and vomiting postsurgery up to Day 24 postsurgery (up to 10-day treatment period plus 14-day 
observation period post last dose for recurrence of symptoms).

Time from end of surgery to first flatus up to Day 10 postsurgery.

Observed plasma concentration of TAK-954 at the end of infusion on Day 1.
Statistical Considerations:
The full analysis set (FAS) will include all subjects who were randomized and received at least 1 dose of study drug 
and have at least 1 postbaseline value for assessment of efficacy. In FAS, subjects will be analyzed by the treatment to 
which they were randomized.
The per-protocol set (PPS) will include all FAS subjects who had no major protocol deviation that could confound the 
interpretation of the primary analyses based on the FAS. The major protocol deviations that lead to a subject’s 
exclusion from the FAS to form the PPS will be specified in the statistical analysis plan. The PPS will be used to 
perform sensitivity analysis for the efficacy endpoints.
The safety analysis set (SAF) will include all subjects who were randomized and received at least 1 dose of 
double-blind study drug. In SAF, subjects will be analyzed according to the treatment they received. 
In the final analyses of efficacy endpoints, for the 2 discontinued treatment arms, only the summary statistics (n, mean, 
SD, median, minimum, and maximum for continuous endpoints; number and percentage of subjects for categorical 
data; the number and percentages of events and censoring, median, minimum, and maximum for time to event 
endpoint) will be provided; for the remaining treatment groups after IA, the inferential statistics (point estimates of 
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interest and 90% CIs and 1-sided p-values) for each treatment group and the TAK-954 doses/regimens in comparison 
with placebo will be provide along with summary statistics.
Primary Efficacy Analysis: The primary endpoint will be analyzed using the Cox proportional hazard model with 
treatment group as a single covariate, with Efron’s method of tie handling, stratified by randomization stratification 
factor. Hazard ratios between TAK-954 doses/regimens and placebo and their 90% CIs based on the Cox model will 
be presented. P-values for the comparisons of TAK-954 doses/regimens and placebo will be calculated using Wald 
chi-square test based on the Cox model and presented. Median time to resolution of upper and lower GI function will 
be estimated by Kaplan-Meier survival analysis. The hazard ratios and median time differences between TAK-954 
doses/regimens and placebo will be used to express the magnitude of treatment effects. The statistical tests will be 
1-sided comparing TAK-954 doses/regimens to placebo. As a sensitivity analysis, the primary endpoint will be 
analyzed using the same method above based on PPS.
Secondary Efficacy Analysis: The secondary endpoints time to tolerance of solid food from the end of surgery, time to 
first spontaneous bowel movement from the end of surgery, time from the end of surgery until ready for discharge, 
time from the end of surgery until the discharge order is written, time from the end of surgery to discharge from 
hospital, and time from the end of surgery to first flatus will be analyzed using similar statistical methods described for 
the primary efficacy analysis.
The comparisons of TAK-954 dose levels and placebo in percent of subjects with POGD ≥5 days and the percent of 
subjects requiring insertion of NG tube postsurgery will be based on the Miettinen and Nurminen’s method stratified 
by randomization stratification factor for risk difference.
Sample Size Justification:
Assuming 80% of subjects will have resolution of POGD at the end of study in the placebo group and 92.5% of 
subjects will have resolution of POGD at the end of study in the active TAK-954 doses, a total of approximately 300 
subjects (100 per treatment group) will provide 80% power with a 0.05 2-sided significance level under Protocol
Amendment 4.
In order to mitigate the statistical, clinical, and operational risks to this study in light of the COVID-19 pandemic, the 
probability of success of the study is re-estimated by blinded assessments using efficacy assumptions of Protocol 
Amendment 4. Specifically, by the removal of the second IA per this amendment and changing the statistical 
significance level from 2-sided 5% to 1-sided 5%, the resulting sample size is an overall total of 50 subjects for each 
remaining arm. Under these revised assumptions and the dropping of 2 arms, an overall total of approximately 180 
subjects for the study will provide approximately 80% probability, for at least 1 remaining TAK-954 treatment arm, 
that TAK-954 is superior to placebo in time to resolution of upper and lower GI function at a 1-sided 5% significance 
level for the final analysis.
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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 vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
The sponsor will select a signatory coordinating Investigator from the investigators who 
participate in the study. Selection criteria for this investigator will include significant knowledge 
of the study protocol, the study drug, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The signatory coordinating investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
5-HT4
5-hydroxytryptamine receptor 4
AE
adverse event
ASA
American Society of Anesthesiologists
AESI
adverse events of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
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 24 hours at steady state
AV
atrioventricular
BfArM
Bundesinstitut für Arzneimittel und Medizinprodukte
BMI
body mass index
bpm
beats per minute
CEC
cardiovascular endpoint committee
COVID-19
coronavirus disease 2019
CRP
C-reactive protein
CV
cardiovascular
ECG
electrocardiogram
eCRF
case report form (electronic or paper)
EQ-5D
EuroQol 5-Dimensions Questionnaire
ERP
enhanced recovery pathway(s)
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic peptide
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
IA
interim analysis
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IL
interleukin
IMC
internal monitoring committee
IND
Investigational Drug Application
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
LOS
length of stay
MCP
monocyte chemoattractant protein
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MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NG
nasogastric
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic
PK
pharmacokinetic
POI
postoperative ileus
POGD
postoperative GI dysfunction
PONV
postoperative nausea and vomiting
PPS
per-protocol set
QD
once daily
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SF-12
12-Item Short Form Health Survey
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
SVT
supraventricular tachycardia
VT
ventricular tachycardia
Takeda
Takeda Development Center Americas, Inc
ULN
upper limit of normal
3.4
Corporate Identification
TDC Europe
Takeda Development Centre Europe Ltd.
TDCA
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDCA, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDCA, as applicable
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4.0
INTRODUCTION
4.1
Background
TAK-954 is a highly selective and potent serotonin type 4 (5-HT4) receptor agonist that has shown 
prokinetic activity throughout the gastrointestinal (GI) tract in experimental models and is being 
developed for the acceleration of GI function recovery postsurgery.
Patients undergoing major abdominal surgery experience a temporary, nonobstructive impairment 
of upper and lower GI motility (function); a condition commonly known as postoperative ileus 
(POI) or postoperative GI dysfunction (POGD) [1]. It is estimated that clinically significant POI 
occurs in 17% of patients undergoing major abdominal surgery [2]. The analysis of a prospective 
database of 1,461 patients undergoing surgery in a high volume colorectal surgical department 
identified POI as 1 of the variables more likely associated with prolonged length of stay (LOS) in 
the hospital. As an average, patients developing symptomatic GI dysfunction in this study had an 
increase LOS of 3.45 days over the expected LOS rates of 8.17 days (interquartile range 4.7-11.9) 
for this cohort [3].
Signs and symptoms associated with postoperative inhibition of GI motility include abdominal 
distension/bloating, nausea and vomiting, lack of bowel sounds, gas and fluid accumulation in the 
bowel, delayed passage of flatus or stool, and intolerance to solid food and need for nasogastric 
(NG) tube insertion when these symptoms occur later in the postoperative period. This 
constellation of signs and symptoms is a leading cause of postsurgical complications and 
readmissions. Multiple factors are thought to contribute to the cause and duration of POGD: 
physical bowel manipulation, secretion of inflammatory mediators, electrolyte/fluid imbalance, 
and excessive use of opioid analgesics. Recent data suggest that upregulation of inflammatory 
pathways during surgery are a major factor in the development of POI and its duration [4].
Stimulation of 5-HT4 receptors may activate anti-inflammatory and prokinetic mechanisms that 
promote earlier GI recovery, prevent, or decrease the duration of GI dysfunction, and facilitate 
earlier hospital discharge. Activation of enteric 5-HT4 receptors is well known to enhance motility 
through-out the GI tract. Postoperative administrations of TAK-954 in a guinea pig model of POI 
led to a dose-dependent attenuation of the surgically-induced delay in GI transit. The potential 
prokinetic properties of TAK-954 have been evaluated in a small study in healthy volunteers 
where the administration of single doses of TAK-954 resulted in significantly shorter time to first 
stool and increases in the number of stools. In addition, the results of a pilot study in critically ill 
patients with increased gastric residual volumes suggested that a single IV dose of 0.5 mg 
consistently shortened gastric emptying of a radiolabeled meal as measured by scintigraphy. 
Additionally, 5-HT4 agonists clinically reverse opioid-induced slowing of intestinal motility [5]. 
Results from a clinical study conducted in China suggest that postsurgical administration of a 
highly selective 5-HT4 agonist in patients undergoing elective GI surgery was able to significantly 
decrease postsurgical recovery time and shorten LOS [6].
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4.2
Rationale for the Proposed Study
To date, 11 clinical studies have been completed:
Phase 1:

Study 0060: a single ascending oral dose study in healthy subjects.

Study 0061: a multiple ascending oral dose study in healthy subjects.

Study 0095: a multiple repeat IV dose study in healthy subjects.

TAK-954-1004: a 2-period crossover drug-drug interaction study of IV TAK-954 with the 
oral cytochrome P450 3A4 inhibitor, itraconazole in healthy subjects.

TAK-954-1005: absorption, distribution, metabolism, and excretion study in healthy male 
subjects.

TAK-954-1006: a single dose study in healthy subjects and subjects with varying degrees 
of hepatic impairment.

TAK-954-1007: a single dose study in healthy subjects and subjects with varying degrees 
of renal impairment.

TAK-954-1009: phase 1, randomized, double-blind, placebo-controlled, single ascending 
dose (SAD), 3-period, incomplete block design study in healthy subjects.
Phase 2:

Study 0082: A phase 2a study in subjects who were critically ill and were being enterally 
fed. 

TAK-954-2002: a double-blind, double-dummy active control study in critically ill 
subjects with EFI. This study was terminated due to challenges with subject recruitment.

TAK-954-2003: a dose-ranging, randomized, parallel, placebo-controlled study to assess 
the effect of TAK-954 on GI and colonic transit in patients with diabetic or idiopathic 
gastroparesis.
These studies have demonstrated acceptable PK characteristics and no major safety issues. This 
study will be the first phase 2 study to test the efficacy and safety of IV TAK-954 for accelerating 
the recovery of GI function postsurgery in patients undergoing open or laparoscopic-assisted 
partial small- or large-bowel resection.
Drug therapy for the prevention and/or management of POI (POGD) is limited. Alvimopan, an 
orally administered, peripherally acting mu-opioid antagonist, has been approved by the Food and 
Drug Administration (FDA) for accelerating the time to upper and lower GI recovery following 
partial large- or small-bowel resection with primary anastomosis. As alvimopan efficacy is related 
to opioid administration, its usefulness may become limited with the increasing practice of 
limiting opioid use during and postsurgery. Alvimopan prescribing is restricted to institutions and 
physicians with specific training (Risk Evaluation and Mitigation Strategy) and for short-term use 
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(up to 7 days for a maximum of 15 doses) due to association of higher incidence of cardiac events 
upon long-term use. Initiatives aimed at reducing LOS, including the expanded use of laparoscopic 
colorectal surgery and enhanced recovery pathways (ERP), have been adopted by many hospitals 
and surgical services. ERP standardize perioperative care to facilitate “fast track” recovery. ERPs 
(including but not limited to early withdrawal of NG suction, early ambulation and provision of 
liquid (Day 1) and solid foods (Day 2), as well decreased opioid use) have had modest success in 
decreasing the duration of POI (1-2 days’ decrease in LOS after colorectal surgery) [7]. Despite 
compliance with ERP and refined discharge criteria, some patients fail early discharge leading to a 
disproportionate use of healthcare resources. Data from a retrospective review of a prospectively 
maintained departmental database of patients at University Hospitals-Case Medical center 
suggested that approximately half of the patients undergoing major laparoscopic colonic surgery 
have a delayed discharge time (>4 days) despite the implementation of standardized early recovery 
plans. Patients with delayed discharge were significantly more likely to present with postoperative 
complications, 30-day reoperation rates and direct hospital cost. Risk factors associated with 
delayed discharge in this study include lower body mass index (BMI), comorbidity, acetylsalicylic 
acid use, prolonged surgical times, increased blood loss during surgery [8]. The significant risk of 
delayed postoperative recovery despite enhanced recovery after surgery implementation was also 
highlighted in another recent study that evaluated the incidence of prolonged POI (defined as the 
need for NG tube reinsertion) in patients undergoing colorectal surgery in a single site center in 
Switzerland. In this study, up to 24.7% of patients needed postoperative reinsertion of NG tube at 
the 3.9 ± 2.9 postoperative day [9]. All these data reinforce the need of additional pharmacological 
measures aimed at preventing POGD as this is the postoperative complication most likely related 
to prolonged length of hospital stay.
Manipulation of the intestines induces an inflammatory response [4]. In a guinea pig model of POI, 
preoperative administration of a 5-HT4 agonist was reported to significantly accelerate and restore 
delayed upper and lower GI transit [10]. Stimulation of 5-HT4 receptors increases vagal efferent 
activity resulting in activation of nicotinic alpha 7 acetylcholine receptors and inhibition of 
resident macrophage and splenic lymphocyte release of inflammatory mediators (eg, tumor 
necrosis factor-alpha) [11]. 
Rationale for Biomarker Evaluation
Increased levels of circulating inflammatory markers like interleukin (IL)-6, IL-10, monocyte 
chemoattractant protein (MCP)-1, high-sensitivity C-reactive protein (CRP), and alarmins like 
S100A8 and S100A12 following surgery have been associated with slower recovery and a longer 
stay in the intensive care unit [12]. In this study, inflammatory mediators, markers of tissue 
damage and motility-associated markers will be measured presurgery and postsurgery to evaluate 
TAK-954 treatment effects, as needed. Importantly, changes in cortisol level associated with 
postoperative nausea [13] will be evaluated as well as levels of glucose-dependent insulinotropic 
peptide (GIP) will also be measured to explore its relationship with vomiting and/or nausea. 
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Rationale for Blood Sampling for DNA
Blood sampling for DNA analysis may be conducted to evaluate the contribution of genetic 
variance on drug response, for example, its efficacy and safety. Participation of study subjects in 
blood sampling for DNA sample collection is optional.
As genomics is an evolving science, currently many genes and their function are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response or diseases, 
which may lead to additional hypothesis-generating exploratory research on stored samples. 
4.3
Benefit-Risk Profile
Study participants undergoing open or laparoscopic-assisted partial small- or large-bowel 
resection and receiving TAK-954 may experience an acceleration of the recovery of GI function 
(motility) postsurgery. This may result in decreased time to tolerance to food ingestion, decreased 
symptoms of slow GI motility (nausea, vomiting, bloating, constipation), earlier hospital discharge, 
and decreased readmissions for symptoms of decreased GI motility.
Overall, TAK-954 is generally well tolerated at oral dosing up to 5 mg (for 10 days) and at IV 
dosing up to 2 mg, based upon overall clinical safety assessment. Aggregate AE review across 
clinical studies conducted to date shows that there were no deaths related to TAK-954 and a very 
low rate of severe AEs or AEs leading to study drug discontinuation. In an aggregate review of 
SAEs, all but 2 SAEs were considered not related to study drug by the investigator: 1 subject 
reported 2 SAEs (anastomotic leak and GI stoma complication) which were assessed as related to 
the blinded study treatment drug (TAK-954 or placebo) by the investigator in this study 
(TAK-954-2004). However, considering the events are common complications of extensive bowel 
resection secondary to underlying malignancy, the 2 serious adverse reactions (SARs) were 
assessed as not related to the blinded study drug by the sponsor. Most AEs were mild or moderate 
in severity, transient, and resolved spontaneously. The most common AEs in subjects receiving 
TAK-954 regardless of doses included headache, nausea, and diarrhea, which were not serious and 
resolved without treatment discontinuation, and without indicating any clear exposure response. 
Across the studies, a few subjects reported AEs of orthostatic hypotension and tachycardia. 
However, these events were nonserious, generally mild or moderate in severity, usually of short 
duration, and resolved spontaneously without significant clinical concern.
The principal mitigation for these risks includes appropriate selection of the study populations, 
detailed safety plan for important potential and identified risks, which permits close monitoring 
and institution of appropriate care as needed, and utilization of experienced staff trained in study 
procedures. 
Overall, the benefit-risk profile is therefore considered appropriate for this study.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s)
The primary objective of this study is to assess the efficacy and safety of IV TAK-954 for 
accelerating the recovery of GI function postsurgery in patients undergoing open or 
laparoscopic-assisted partial small- or large-bowel resection.
5.1.2
Secondary Objectives
The secondary objectives of this study are:

To determine efficacy and safety of preoperative dosing of IV TAK-954 relative to 
preoperative and postoperative regimens of up to 10 days of IV TAK-954 for accelerating the 
recovery of GI function postsurgery.

To determine the relative efficacy and safety of 0.1 and 0.5 mg IV TAK-954 given either 
preoperatively alone or preoperatively and postoperatively compared with placebo of up to 
10 days or resolution of GI dysfunction postsurgery for accelerating the recovery of GI 
function postsurgery.

To determine the PK of TAK-954 in patients undergoing major abdominal surgery.
5.1.3
Exploratory Objectives
The exploratory objectives are:

To assess the effect of IV TAK-954 on circulating markers of inflammation, including but not 
limited to IL-6, IL-10, MCP-1, and CRP postsurgery.

To assess the effect of IV TAK-954 on circulating markers associated with GI motility and/or 
nausea.

To gain preliminary estimates of the incidence rate of postoperative complications and 
prolonged POGD (≥5 days) based on the type of surgery (laparoscopic vs open surgery), use of 
opioids, duration of surgical procedure, and ASA scores.

To gain preliminary estimate of the effect of TAK-954 in preventing recurrence of GI 
dysfunction postsurgery.

To gain preliminary estimate of the effect of TAK-954 in preventing POGD complications.
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5.2
Endpoints
5.2.1
Primary Endpoint
The primary efficacy endpoint is time from the end of the surgery to resolution of upper and lower 
GI function (ie, time to tolerance of solid food [defined as first occurrence of no vomiting or no 
clinically significant nausea for 1 calendar day after a solid meal] and time to first spontaneous 
bowel movement, whichever occurs later) up to Day 10 postsurgery.
5.2.2
Secondary Endpoints
The secondary endpoints for this study are:

Time from the end of the surgery (time the incision is closed) until ready for discharge (defined 
as the time until the subject presents effective intestinal transit [spontaneous bowel movement], 
tolerates solids without vomiting or clinically significant nausea for 1 calendar day after a solid 
meal, has satisfactory pain control with oral analgesics, and is medically stable/free of 
complications).

Time from the end of surgery until the discharge order is written.

Time from the end of the surgery to discharge from hospital.

Time from end of surgery to tolerance of solid food (defined as first occurrence of intake of 
solids without vomiting or clinically significant nausea for 1 calendar day after a solid meal) up 
to Day 10 postsurgery.

Time from end of surgery to first spontaneous bowel movement (defined as a stool not induced 
by the use of enemas or laxatives) up to Day 10 postsurgery.

Percent of subjects with POGD ≥5 days defined as subjects unable to tolerate solid foods, take 
anything by mouth, or requiring insertion or reinsertion of NG at or after 5 days postsurgery.

Percentage of subjects requiring insertion of NG tube postsurgery, for drainage and symptom 
relief in case of persistent nausea and vomiting postsurgery up to Day 24 postsurgery (up to 
10-day treatment period plus 14-day observation period post last dose for recurrence of 
symptoms).

Time from end of surgery to first flatus up to Day 10 postsurgery.

Observed plasma concentration of TAK-954 at the end of infusion on Day 1.
5.2.3
Safety Endpoints
Safety and tolerability will be evaluated based on the occurrence of AEs, physical examination 
findings, vital signs and weight, ECGs, and clinical laboratory parameters (chemistry, 
hematology). 
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5.2.4
Exploratory Endpoints
The exploratory endpoints for this study will be:

Change in circulating inflammatory markers including but not limited to IL-6, IL-10, MCP-1, 
and CRP, preoperatively compared with postoperatively across different treatment groups.

Change in GIP and cortisol preoperatively compared with postoperatively across different 
treatment groups.

Incidence rate of POGD recurrence for 14 days post last dose.

Percentage of subjects with unplanned hospital readmissions due to recurrence of POGD.

Percentage of subjects with postoperative complications, such as pneumonia, acute kidney 
failure, or documented anastomotic leak.

Percentage of subjects requiring reoperation due to postoperative complications.

Health-related quality of life as measured by 12-Item Short Form Health Survey (SF-12) and 
EuroQol 5-Dimensions Questionnaire (EQ-5D).

Percentage of subjects with postoperative nausea and vomiting (PONV) within 24 hours after 
surgery, from Day 2 until discharge and at follow-up; defined as patients presenting with 
emetic events (nausea, vomiting, or retching) or requiring use of antiemetics.

Peak nausea severity score from Day 1 until discharge using a numerical rating scale.

Time from the end of the surgery to the first insertion of NG tube (for those requiring insertion 
of NG tube postsurgery).

Percentage of subjects presenting complications or prolonged POGD (≥5 days) based on 
opioid use, type of surgery, duration of the surgical procedure, and ASA scores.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This phase 2, randomized, placebo-controlled, parallel 5-group, double-blind study is designed to 
determine: (1) if TAK-954 decreases the duration of GI dysfunction in patients undergoing major 
abdominal open or laparoscopic-assisted surgeries that involve significant bowel manipulation, (2) 
whether preoperative dosing alone or a preoperative and postoperative dosing regimen is the most 
effective dosing regimen to decrease the duration of POGD and improve clinical outcomes, and (3) 
the most appropriate dose and dosing regimen to advance into phase 3.
Subjects will be randomized in a 1:1:1:1:1 ratio into 1 of 5 parallel treatment groups:

Regimen 1: Placebo (normal saline 100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function (ie, resolution of POGD) or for up to 
10 days.
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
Regimen 2: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 3: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 4: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to
10 days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to 
10 days.
Subject randomization will be stratified by laparoscopic and open surgery procedures.
With this Protocol Amendment 5, the planned total sample size is approximately 180 subjects. 
Two of the above TAK-954 regimens are discontinued based on IMC recommendations. As a 
result, eligible subjects will be equally randomized to into 1 of 3 of the remaining parallel 
treatment groups:

Regimen 1: Placebo (normal saline 100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function (ie, resolution of POGD) or for up to 
10 days

Regimen 3: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to 
10 days.
It is standard of practice for the postoperative care of patients after colorectal surgery to implement 
an ERP to reduce the time to recovery of GI function (motility). To provide a consistent ERP as 
baseline therapy for all subjects, they will receive the same core features of an ERP for 
postoperative care as outlined below:
Core ERP:

Minimize opioid use while maintaining adequate pain control through use of multimodal 
analgesia. Suggested analgesics include opioid alternatives, such as nonsteroidal 
anti-inflammatory drugs (eg, ketorolac tromethamine IV), acetaminophen (paracetamol), or 
oral pregabalin, when possible. It is recommended that at least 2 different analgesics with
different mechanism of action are tried and failed before prescribing opioids.

Maintenance of euvolemia and normal salt and electrolyte state in perioperative period.

No routine use of prophylactic NG tubes postsurgery. NG tubes should only be used if there is 
a documented medical reason to justify them.
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
Use of a standardized risk-based strategy for PONV prophylaxis: use of preoperative 
antiemetic prophylaxis in patients with 1 or more risk factors of the simplified Apfel Score 
(female gender, planned postoperative use of opioids, nonsmokers, history of PONV/motion 
sickness).

Early oral feeding postsurgery when possible. Clear liquids after the surgery on Day 1, 
advancing to soft diet on Day 2 if tolerant to liquids (no nausea or vomiting).

Early mobilization starting after the surgery on Day 1 when possible.
Schematics of the study design prior to Protocol Amendment 5 can be found in Figure 6.a and with 
the discontinuation of 2 treatment regimens and removal of the second IA in Figure 6.b. A 
schedule of assessments is listed in Appendix A.
Figure 6.a
Schematic of Study Design Prior to Protocol Amendment 5
Abbreviations: IA, interim analysis; PBO, placebo.
PBO
T1*
T2*
T3*
25
25
25
25
IA #1 
Decisions based 
on efficacy and 
safety of each arm 
(potential study 
modification 
including futility, 
dose adjustment, 
dose/dosing 
regimen decisions, 
and sample size 
adjustments).
Validation of 
power calcula ion
Doses/regimens may be modified.
PBO
TO1**
TO2**
+ 25, Total: 50
+ 25, Total: 50
+ 25, Total: 50
25 subjects/arm
Total: 125 subjects
Add 25 subjects/arm
Total: up to 225 subjects
IA #2
Decisions based 
on efficacy and 
safety of each arm 
(Goal is to identify 
the most 
promising/safe 
dose/regimen).
Valida ion IA #1
PBO
+50, Total: 100
Add 50 subjects/arm
Total: up to 375 subjects
TOX***
+50, Total: 100
TOY****
+50, Total: 100
(Possible)
T1 = TAK-954 0.1 mg/100 mL infusion preoperative and daily
T2 = TAK-954 0.5 mg/100 mL infusion preoperative and daily
T3 = TAK-954 0.1 mg/100 mL infusion preoperative only 
T4 = TAK-954 0.5 mg/100 mL infusion preoperative only 
Doses/regimens may be modified.
**TO1 & TO2 & TO3 = Optimal 
dose carried over after IA #1
***TOX = Optimal dose continues after IA #2.
****TOY = Could continue if deemed 
valuable as alternative dose.
T4*
25
TO3**
+ 25, Total: 50
(Possible)
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Figure 6.b
Schematic of Study Design By Protocol Amendment 5
Abbreviations: IA, interim analysis; PBO, placebo.
Criteria for resolution of upper and lower GI function is time to first tolerance of solid food 
(defined as no vomiting or no clinically significant nausea for 1 calendar day after a solid meal) 
and time to first spontaneous bowel movement, whichever occurs later, up to Day 10 postsurgery. 
Following hospital discharge, subjects will be instructed to contact their physician if they have 
recurring symptoms suggestive of POGD to evaluate the need for hospital readmission in case of 
relapse. All subjects will return to the clinic 14 days (±4 days) post last dose; however, during the 
COVID-19 public health emergency, the follow-up visit 14 days post last dose may be conducted 
via phone call (eg, collection of AEs, concomitant medications, and monitoring) to extend 
flexibility to study subjects. In the case of a phone call follow-up, physical examination (including 
neurology examination), vital signs, or pregnancy test would not be collected; however, AEs will 
be assessed, including a safety check on any emerging clinical signs or symptoms. Subjects may be 
requested to return to the site for further safety assessment, due to reported AEs, at the 
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investigator’s discretion. The type of visit (whether clinic visit or phone call) must be recorded in 
the study records. Quality of life assessments will be completed by the subject in their home on the 
same day as the safety follow-up call and completed questionnaires will be mailed to the clinic. 
Subjects will be contacted by phone 30 (±3 days) and 90 (±7 days) days posttreatment for a safety 
follow-up.
Two preplanned IAs will be conducted when a priori enrollment goals have been achieved. 
Bayesian approach will be applied after these IAs for decision making for potential study 
modification including futility, dose and dosing regimen decision, and sample size adjustment. In 
case dose modification is needed after the IA, the maximal dose for potential modification of 
doses/regimens will be 1.0 mg. The duration of drug administration (up to 10 days postsurgery) 
will not be changed. By this protocol amendment, the second IA is removed from the protocol.
6.2
Justification for Study Design, Dose, and Endpoints
Rationale for Study Design
The proposed adaptive design with bayesian approach has several benefits over traditional design 
and frequentist method. Adaptive designs have become popular in clinical trials because of its 
advantages of flexibility and efficiency gains, some of which also have the significant advantage 
of enrolling fewer patients to treatment arms with inferior outcomes.
Rationale for Dose
TAK-954 IV doses of 0.1 and 0.5 mg QD preoperatively and postoperatively for up to 10 days and
0.1 and 0.5 mg single doses preoperative administration were selected to be studied in this dose 
and dosing regimen study. These doses are expected to allow the characterization of the 
exposure/response (efficacy and safety) relationship for TAK-954. The exposure/response data 
generated from these dosing regimens will provide information for selecting optimal doses for 
future studies and dosing regimen and to maximize benefit/risk ratio. Several factors have been 
taken into account when selecting the doses and dosing regimen mentioned above, including 
safety, tolerability, PK, and pharmacodynamic (PD) data from healthy volunteers and critically-ill 
patients with delayed gastric emptying. TAK-954 was generally well tolerated in healthy 
volunteers following 0.5 mg IV administered for 5 days. TAK-954 0.1 and 0.5 mg doses appeared 
to reduce the time to first bowel movement and increase the number of bowel movements on the 
first day of dosing in healthy subjects. When compared with metoclopramide 10 mg IV every 6
hours, a single dose of 0.5 mg IV TAK-954 also demonstrated a consistent pattern to enhance 
gastric emptying in critically ill patients with delayed gastric emptying.
All available efficacy, safety, and tolerability data will be considered to determine potential 
changes to dose or regimen after each IA. The potential duration of drug administration (up to 
10 days postsurgery) will not be changed. Additionally, the basic regimen (preoperation 
administration and postoperation administration) will not be altered.
Preliminary data suggest that a prokinetic and anti-inflammatory effect is achieved with 0.5 mg. 
Additionally, results from a completed scintigraphy study assessing the effect TAK-954 on gastric 
emptying, small bowel and colonic transit, as well as the safety and tolerability of doses of 0.1, 0.3, 
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and 1.0 mg QD IV in patients with gastroparesis (TAK-954-2003), will be considered during the 
IA. This information, along with the IA results, will be used to decide if adjustments to the current 
doses tested in the TAK-954-2004 study are warranted. 
The maximum dose that could potentially be used in the TAK-954-2004 study is 1.0 mg QD by IV 
administration. Based on the principle of superposition, the predicted maximum concentration 
during a dosing interval, at steady state (Cmax,ss) and area under the concentration-time curve from 
time 0 to 24 hours, at steady state (AUC24,ss) for TAK-954 1.0 mg QD IV dosing provides an 
approximately 41-fold/851-fold margin relative to total/free Cmax at the no-observed-effect level in 
the dog cardiovascular (CV) study, 468-fold margin relative to AUC24 in the rat 13-week 
repeat-dose study at the no-observed-adverse-effect level (NOAEL), and 250-fold margin relative 
to AUC24 in the rabbit embryo-fetal-development study at the NOAEL, respectively. These 
exposures are approximately one-third to one-half of the exposures that were achieved with 5 mg 
QD oral dosing for 10 days in healthy subjects (maximum tolerated dose).
Rationale for Endpoints
All patients undergoing an abdominal surgical procedure will inevitably develop a transient 
episode of impaired GI motility (traditionally referred to as POI) and stasis of the intraluminal 
contents [14]. In some cases, this may result in nausea, vomiting, bloating, delayed passage of 
stool and inability to tolerate liquid or solid foods. Normally, inhibition of small bowel motility is 
transient and the stomach recovers within 24 to 48 hours, whereas colonic function takes 48 to 72 
hours to return [14]. The duration of this impaired motility reflects the clinical recovery of the 
patient. Determination of the end of POGD (or POI) has been somewhat controversial as different 
studies have tried to identify the return of normal bowel motility with unreliable and poorly 
specific clinical endpoints such as time to first flatus or return of bowel sounds. Using scintigraphy, 
van Bree et al [15] have shown that the return of gastric emptying is reflective of the ability to 
tolerate solid food, and that the occurrence of the first solid stool reflects return of lower GI 
motility. The combined outcome measure of tolerance of solid food and having had defecation 
(area under the concentration-time curve = 0.9, SE = 0.04, 95% CI = 0.79-0.95, p <0.001) best 
indicated recovery of GI transit with a positive predictive value of 93% (95% CI = 78-99). They 
further validated this endpoint using data from a multicenter trial of 320 segmental colectomy 
patients in which multiple regression analysis revealed that time to first stool and solid food 
tolerance best predicted the duration of hospital stay. Therefore, the primary endpoint in this study 
will assess the duration of time to tolerance of solid food and time to the first spontaneous bowel 
movement (whichever occurs later) which reflects a clinically meaningful return of GI 
function/motility.
6.3
End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
study, or is lost to follow-up (ie, the investigator is unable to contact the subject).
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6.4
Premature Termination or Suspension of Study or Study Site
6.4.1
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.

Futility demonstrated at IA.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.4.2
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 enrollment or performance of the study, or as otherwise permitted by the contractual 
agreement.
6.4.3
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)/independent ethics committee 
(IEC) 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.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is scheduled to undergo a laparoscopic-assisted, or open partial small- or 
large-bowel, resection.
4. The subject is male or female and is at least 18 years old.
5. The subject’s ASA physical status classification is ASA 1 to 3.
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6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use a highly effective method of contraception* from signing of informed 
consent throughout the duration of the study and for up to 30 days posttreatment.
*Definitions and highly effective methods of contraception are defined in 
Section 9.1.13 and reporting responsibilities are defined in Section 9.1.14.
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 received any investigational compound within 30 days prior to screening.
2. The subject has received TAK-954 in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
4. The subject has significant mechanical bowel obstruction that is not expected to resolve after 
the surgery, short bowel syndrome, pre-existing clinically significant GI motility disorder (eg, 
gastroparesis, scleroderma, chronic intestinal pseudo-obstruction), uncontrolled diabetes 
(glycosylated hemoglobin [HbA1c] >10%), has an active gastric pacemaker, or requires 
parenteral nutrition.
5. The subject had previous major abdominal surgery (eg, gastrectomy, gastric bypass, gastric 
sleeve, lap banding, Whipple, pancreatic resection, total/subtotal colectomy, hemicolectomy, 
extensive bowel resection). 
6. The subject has a history of radiation therapy to the abdomen or pelvis.
7. The subject is scheduled to undergo any of the following surgeries: low anterior resection, total 
or subtotal colectomy, colostomy, ileostomy, or reversal of stoma or has a diagnosis that 
requires rectal resection (eg, tumors in the anorectum) and will likely require lower anterior 
resection surgery. Subjects with planned surgery for which there is no anticipated significant 
rectal resection and is, therefore, likely to preserve anorectal function and continence 
postsurgery, will likely be eligible for inclusion in the study if they meet all the study 
inclusion/exclusion criteria (eg, subjects with lesions not involving the rectum [sigmoid colon 
and above]). 
8. The subject has pre-existing hepatic disease that meets Child-Pugh Class B (moderate; total 
score 7 to 9 points) or C (severe; total score 10 to 15 points).
9. The subject has alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) >3 × upper limit of normal (ULN), or total bilirubin >2 × ULN.
10. The subject has an estimated glomerular filtration rate <30 mL/min.
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11. The subject has received alvimopan, erythromycin, prucalopride, metoclopramide, 
domperidone, cisapride, mosapride, renzapride, or azithromycin in the 24 hours prior to 
starting study drug.
12. The subject has a resting heart rate of <50 beats per minute (bpm).
13. The subject has clinically significant ECG abnormalities indicative of cardiac conduction 
abnormality or acute cardiac instability as determined by the investigator at screening; more 
than first degree atrioventricular (AV) block; >5 beats of nonsustained ventricular tachycardia 
(VT) at a rate >120 bpm; or ECG changes consistent with acute myocardial ischemia or 
infarction.
14. The subject has a QT interval with Fridericia correction method (QTcF) ≥450 msec or other 
factors that increase the risk of QT prolongation or arrhythmic events at screening. The records 
of subjects with bundle branch block and a prolonged QTcF should be reviewed by a medically 
qualified person in consultation with the medical monitor and the sponsor for potential 
inclusion.
15. The subject has known COVID-19 infection, or suspected COVID-19 infection (as assessed by 
the investigator).
16. The subject has any other significant uncontrolled organic or systemic medical condition or 
social circumstance that, in the investigator’s opinion, would mean it was not appropriate for 
the subject to participate in this clinical study.
17. The subject is scheduled for abdominal surgery that is classified as emergency.
18. The subject had acute myocardial infarction or ischemia within the past 12 months. Subjects 
with increased cardiac risks for surgery including coronary artery disease or prior myocardial 
infarction and evidence of reduced left ventricular function or history of angina should be 
assessed by the investigator for stability and control of their cardiac condition and risk of 
surgery, and excluded if in the investigator’s opinion, participation in the study is not 
considered appropriate. The sponsor should be consulted if subjects with these conditions are 
considered by the investigator to be acceptable.
19. The subject had pulmonary embolism, deep venous thrombosis, or mechanical ventilation for 
any medical condition within the past 12 months. Subjects with a history of multiple venous 
thrombosis or pulmonary embolic events, history of a hypercoagulable condition, history of 
severe exacerbation for chronic obstructive pulmonary disease or evidence of pulmonary 
hypertension should be assessed by the investigator for stability and control of their conditions 
and risk of surgery, and excluded if in the investigator’s opinion, participation in the study is 
not considered appropriate. The sponsor should be consulted if subjects with these conditions 
are considered by the investigator to be acceptable.
7.3
Excluded Medications
The following medications are excluded from 24 hours prior to starting study drug to 5 days post 
last dose of study drug.
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Laxatives (preoperative bowel preparations are not excluded).
Prokinetic agents: domperidone, erythromycin, azithromycin, and 5-HT4 agonists (cisapride, 
mosapride, prucalopride, renzapride, and metoclopramide).
µ-Opioid antagonist: Alvimopan.
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 electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.19.
1. Treatment discontinuations due to an AE: The subject has experienced an AE that requires 
early termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the AE. Specific events that require 
treatment discontinuation (see Section 10.1.6) include:

Prolonged QT: Second episode of Grade 2 (QTcF >480 and ≤500 msec), any occurrence of 
Grade 3 (QTcF >500 msec, or >60 msec change from baseline) or Grade 4 (Torsades de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia).

Second or third-degree heart block: Treatments with study drug may be continued in 
second-degree heart block Mobitz I (Wenckebach) after medical monitor review.

Any occurrence of Grade 4 (life-threatening) supraventricular tachycardia (SVT) that is 
considered related by the investigator.

Suspected serotonin syndrome.

Liver test abnormalities: Treatment with study drug should be discontinued in subjects 
who develop ALT or AST >3 × ULN concurrently with total bilirubin >2 × ULN while on 
treatment with study drug. These findings should be reported to the sponsor as a serious 
adverse events of special interest (AESI). The investigator must contact the medical 
monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis, other acute liver disease, or medical history/concurrent 
medical conditions. In addition, the investigator should contact the medical monitor for 
any increase in liver tests without clear etiology.

Known COVID-19 infection.
2. 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.
3. Subject did not receive 2 or more doses of the assigned randomized treatment.
4. If the subject, due to intraoperative circumstances, has surgery that results in a significant 
resection of rectal tissue, a >50% resection of colon tissue, or an ostomy, study drug dosing 
should be discontinued.
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5. Voluntary withdrawal. The subject wishes to withdraw from the study or study drug. 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). Similarly, lack of efficacy 
should not be recorded in the “voluntary withdrawal” category. Additional efforts should be 
made and documented to encourage subject to participate in the follow-up portion of the study.
6. Study termination. The sponsor, IRB, IEC, 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 9.1.14.
8. Lack of efficacy. The investigator has determined that the subject is not benefiting from study 
treatment; and, continued participation would pose an unacceptable risk to the subject. 
9. 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 drug participation at any time during the study 
when the subject meets the study drug 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 study drug 
termination must be recorded by the investigator. 
In addition, efforts should be made to perform all procedures scheduled for the early termination 
visit. Every effort should be made to perform the follow-up visits at 14, 30, and 90 days post last 
dose for every dosed subject, as noted in the Schedule of Study Procedures (Appendix A). For 
subjects who did not receive study drug, the follow-up visits do not need to be completed. 
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 
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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 normal saline (0.9% sodium chloride for injection), for IV infusion. 
Normal saline is used as placebo.
TAK-954 cartons and vials will be affixed with labels that are in accordance with regulatory 
requirements.
8.1.1.2
Ancillary Materials
All ancillary supplies will be provided by either the site or the sponsor, based upon availability. If 
provided by the sponsor, unused ancillary supplies will be accounted for and disposed of as 
directed by the sponsor or a designee.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is used or 
authorized for destruction by the sponsor or designee. 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. The required 
storage condition for TAK-954 study drug is refrigeration between 2°C and 8°C. 
8.1.3
Dose and Regimen
Subjects will be randomized 1:1:1:1:1 into 1 of 5 treatment groups. Adjustments to the treatment 
groups may be made based on IA results.
Following the discontinuation of 2 treatment groups (see Section 6.1), subjects will be randomized 
to 1:1:1 into 1 of 3 remaining treatment groups by Protocol Amendment 5 (see Section 6.1).
Additional information regarding the dosing instructions for TAK-954 can be found in the 
pharmacy manual.
Table 8.a describes the dosing regimens in the protocol and Table 8.b describes the dosing 
regimens remaining after discontinuing 2 dosing groups as clarified in this protocol amendment.
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Table 8.a
Dose and Regimen Prior to Protocol Amendment 5
Treatment 
Group
Dose
Treatment Description
1
Placebo (100 mL saline infusion over 
60 minutes)
Given preoperation and daily postoperation for up to 10 days 
or until return of upper and lower GI function.
2
TAK-954 (0.1 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily postoperation for up to 10 days 
or until return of upper and lower GI function.
3
TAK-954 (0.5 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily postoperation for up to 10 days 
or until return of upper and lower GI function. 
4
TAK-954 (0.1 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily placebo infusions postoperation 
for up to 10 days or until return of upper and lower GI 
function.
5
TAK-954 (0.5 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily placebo infusions postoperation 
for up to 10 days or until return of upper and lower GI 
function.
Abbreviations: GI, gastrointestinal.
Table 8.b
Dose and Regimen as a Result of Protocol Amendment 5
Treatment 
Group
Dose
Treatment Description
1
Placebo (100 mL saline infusion over 
60 minutes)
Given preoperation and daily postoperation for up to 10 days 
or until return of upper and lower GI function.
3
TAK-954 (0.5 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily postoperation for up to 10 days 
or until return of upper and lower GI function. 
5
TAK-954 (0.5 mg/100 mL infusion 
over 60 minutes)
Given preoperation and daily placebo infusions postoperation 
for up to 10 days or until return of upper and lower GI 
function.
Abbreviations: GI, gastrointestinal.
On Day 1, the completion of the infusion should occur within 3 hours of the start of surgery 
(induction of anesthesia). Subsequent doses (Days 2 to 10, if required) should be approximately 24 
hours (±5 hours) from the start of the prior infusion. If a subsequent dose cannot be administered 
during this window, it should be skipped. 
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. 
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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.
TAK-954 has been investigated in clinical studies up to 20 mg orally. AEs observed at 5 mg orally 
(with a mean exposure approximately 4-fold higher than that for IV dosing at 0.5 mg) or higher 
included mild orthostatic hypotension in 1 subject after they received a single oral 5 mg dose and 
mild AV dissociation in 2 subjects after they received a single oral 10 mg dose. In the event of an 
IV overdose, discontinue the treatment of study drug, treat the subject symptomatically and 
provide supportive care as needed.
8.2
Study Drug Assignment and Dispensing Procedures
In order to maintain the blind, all study site personnel except the investigational pharmacist or 
designee will be blinded to subject treatment assignments for the duration of the study. A member 
of the investigator staff will utilize the IRT to randomize the subject into the study. During this 
contact, the staff member will provide the necessary subject-identifying information, including the 
subject number assigned at screening. Subjects will be assigned in a 1:1:1:1:1 ratio to receive the 
treatments or placebo, TAK-954 0.1 or 0.5 mg preoperation, or TAK-954 0.1 or 0.5 mg 
preoperation and postoperation daily for up to 10 days or until the return of upper and lower GI 
function. By Protocol Amendment 5, subjects will be assigned in a 1:1:1 ratio to receive the 
treatments or placebo, TAK-954 0.5 mg preoperation, or TAK-954 0.5 mg preoperation and 
postoperation daily for up to 10 days or until the return of upper and lower GI function. The study 
drug assignment will be emailed to the unblinded pharmacist only. Unblinded investigator staff 
should not be involved with any study procedures or assessments other than those related to study 
drug management (eg, dispensing, preparation, accountability, etc.). Similarly, blinded 
investigational staff should not have access to pharmacy documentation or interact with pharmacy 
staff in a manner which could unblind them to subject treatment assignment. 
Subject randomization will be stratified by laparoscopic and open surgery procedures.
Subjects will be assigned to receive their treatment according to the randomization schedule 
allocated to each study site. 
Specific procedures related to treatment assignment/dispensation, requests for resupply of study 
drug, or reporting of lost or damaged shipments of study drug are outlined in the study manual. 
8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor/ the designee of the sponsor will generate the 
randomization schedule and will provide it to the IRT vendor before the start of this study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
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8.4
Study Drug Blind Maintenance
The study drug blind will be maintained using the IRT.
Since the maintenance of the blind may be compromised because of results from drug 
concentrations and/or PD assessments, such results should not be disclosed before formal 
unblinding of study. In the event that results must be reported to the investigator before breaking 
the blind, all efforts should be made to maintain the blind (eg, as changing a medication 
identification [ID] number in order to avoid identification of subjects by the laboratory site 
personnel).
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 assessments should be performed, if possible, before 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.
For unblinding a subject, the study drug blind can be obtained by the investigator, by accessing the 
IRT. 
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. 
Placebo PK samples will not be analyzed; therefore, the randomization code will be sent to the 
analyzing laboratory.
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.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment as instructed per the documentation 
accompanying the shipment. If there are any discrepancies between the packing list versus the 
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actual product received, the sponsor or its designee must be contacted to resolve the issue. The 
packing list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot/medication ID used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, expiry date and amount dispensed including initials, and signature of 
the person dispensing the drug. The log should include all required information as a separate entry 
for each subject to whom sponsor-supplied drug is dispensed. 
Before site closure or at appropriate intervals, a representative from the sponsor or its designee will 
perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied drugs 
are returned to the sponsor or its designee for destruction or destroyed locally. The investigator or 
designee will retain a copy of the documentation regarding sponsor-supplied drug accountability, 
return, and/or destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction or destroyed locally.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, the 
sponsor or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites.
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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. Informed consent may be performed in clinic or 
remotely using electronic signature where allowed by site IRBs/IECs.
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 or age, sex, ethnicity (as 
described by the subject or subject’s representative), 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. This includes clinically significant laboratory, ECG, or physical examination 
abnormalities noted at the screening examination, according the judgment of the investigator. 
History of chronic obstructive pulmonary disease, chronic kidney and liver disease, diabetes, and 
CV comorbidity should be documented. 
Medication history information to be obtained includes all medication and any medication relevant 
to eligibility criteria stopped at or within 24 hours prior to signing of informed consent.
9.1.3
Physical Examination Procedure (Including Neurology Examination)
A baseline physical examination (defined as the assessment before first dose of study drug) will 
consist of the following body systems: (1) CV system; (2) respiratory system; (3) GI system; 
(4) nervous system looking mainly for hypertonicity, reflexes, and clonus; and (5) other. Physical 
examinations collected as standard of care (SOC) within 21 days of randomization may be used for 
study screening purposes. If physical examinations are collected as SOC on the day of surgery but 
before informed consent, they may be used for screening/baseline purposes as long as the results 
are assessed for eligibility before randomization. Any clinically significant changes from the 
baseline examination will be recorded as an AE.
A targeted neurological examination looking for hypertonicity, reflexes, and clonus will be 
performed by medically qualified personnel at screening, baseline (preinfusion Day 1), on Days 2 
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and 5, on the last day of study treatment or early termination (as applicable), and at the follow-up 
visit (14 days post last dose).
During the COVID-19 public health emergency, the follow-up visit at 14 days (±4 days) post last 
dose may be conducted at the clinic or via phone call (eg, collection of AEs, concomitant 
medications, and monitoring), to extend flexibility to study subjects. In the case of a phone call, a 
physical examination (including neurology examination) would not be collected; however, AEs 
will be assessed, including a safety check on any emerging clinical signs or symptoms. Subjects 
may be requested to return to the site for further safety assessment, due to reported AEs, at the 
investigator’s discretion. The type of visit (whether clinic visit or phone call) must be recorded in 
the study records.
9.1.4
Weight, Height, and BMI
A subject should have weight and height collected as per the SOC. BMI will be derived from the 
subject’s height and weight. 
9.1.5
Vital Sign Procedure
Vital signs will include blood pressure (systolic and diastolic) and pulse (bpm). Subjects should 
have rested for at least 5 minutes before vital sign assessment. Vital signs collected as SOC within 
21 days of randomization may be used for study screening purposes. If vital signs are collected as 
SOC on the day of surgery but before informed consent, they may be used for screening/baseline 
purposes as long as the results are assessed for eligibility before randomization.
Vital signs will be collected at the following time points: screening, presurgery before and at the 
end of study drug infusion on Day 1, on Days 2 to 10 (ie, at the end of study drug infusion in the 
morning and in the evening), and at the follow-up visit (14 days post last dose). The time window 
will be 12 hours ±4 hours. On the day of surgery, vital signs will be monitored as part of the SOC. 
Clinically abnormal vital signs will be captured as an AE as per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
During the COVID-19 public health emergency, the follow-up visit at 14 days post last dose may 
be conducted at the clinic or via phone call (eg, collection of AEs, concomitant medications, and 
monitoring), to extend flexibility to study subjects. In the case of a phone call, vital signs would 
not be collected; however, AEs will be assessed, including a safety check on any emerging clinical 
signs or symptoms. Subjects may be requested to return to the site for further safety assessment, 
due to reported AEs, at the investigator’s discretion. The type of visit (whether clinic visit or phone 
call) must be recorded in the study records.
9.1.6
Primary Efficacy Measurement
The length of time from the end of the surgery to the occurrence of the toleration of solid foods 
(defined as first occurrence of no vomiting or no clinically significant nausea for 1 calendar day 
after a solid meal) and time to first spontaneous bowel movement, whichever occurs later. 
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If a subject meets the primary endpoint after midnight, the study procedures outlined in the 
Schedule of Study Procedures (Appendix A) can be completed the next day. If a subject meets the 
primary endpoint in morning and is discharged later that day, this is considered a minor protocol 
deviation. Note that the exact times of first spontaneous bowel movement and tolerance to solid 
food should be documented in source file and reported in the eCRF.
9.1.7
Study Surgery
The reason for surgery, the type of surgery, ASA scores, start and stop times, approximate length 
of bowel removed (cm), and the duration of the surgery will be documented.
9.1.8
Clinical Assessments
The investigator is responsible for assessing the following on a daily basis from Day 1 to 
discharge:

Time to first spontaneous bowel movement and the approximate number of bowel movements 
each day.

Tolerance to fluid intake (only until tolerance is achieved).

Tolerance to soft food (only until tolerance is achieved).

Tolerance to solid food (only until tolerance is achieved).

Presence of vomiting/retching with the number of episodes in previous 24 hours, approximate 
volume, and if bilious.

Presence and severity of nausea measured through a numerical rating scale from 0 (no nausea) 
to 10 (worst possible nausea) as in Figure 9.a.
Figure 9.a
Numerical Rating Scale

Assessment of abdominal distension, including tympany if present.

Presence of flatus (only until first episode of flatus).
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
Need for reinsertion of nasogastric tube in the postoperative period for NG suction.

Readiness for hospital discharge.
9.1.9
Documentation of Concurrent Medical Procedures
All procedures (eg, computed tomography scan, biopsy, insertion of the NG tube, aspiration of 
fluid) conducted after signing the informed consent form and up to Day 10 of study drug 
administration are to be recorded on the eCRF. 
9.1.10
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug, including antiemetics 
used for prophylaxis or treatment of PONV, anesthetics, analgesia, or treatment for postoperative 
complications. These may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by the sponsor. All concomitant medications received 
from the time of obtaining informed consent will be recorded. During the follow-up visit 14 days 
(±4 days) post last dose, subjects will be asked whether they have taken any medication, including 
vitamin supplements, over-the-counter medications, and oral herbal preparations, and this must be 
recorded in the eCRF. 
9.1.11
Documentation of Core ERP
Sites will document that they are following core ERP for each randomized subject. Adherence to 
core ERP will be evaluated based on the Core ERP criteria outlined in Section 6.1.
9.1.12
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Results of 
clinical laboratory assessments collected as SOC within 21 days of randomization or HbA1c 
collected within 30 days of informed consent may be used for study screening purposes. If clinical 
laboratory samples are collected as SOC on the day of surgery but before informed consent, they 
may be used for screening/baseline purposes as long as the results are assessed for eligibility 
before randomization. Details of these procedures and required safety monitoring will be given in 
the site operations 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
RBC
WBC
Hemoglobin
Hematocrit
Platelets
Prothrombin time
INR
Erythrocyte sedimentation rate
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Chloride
Creatine kinase
GGT
Potassium
Sodium
CRP
Other:
Serum
Serum or urine
HbA1c a
Beta hCG (for pregnancy, female subjects only) a
ALT, alanine aminotransferase; AST, aspartate aminotransferase; C-reactive protein, CRP; GGT, γ-glutamyl 
transferase; HbA1c, glycosylated hemoglobin, hCG, human chorionic gonadotropin; INR, international normalized 
ratio; RBC, red blood cell; WBC, white blood cell.
a Collected at screening only. An HbA1c collected within 30 days of screening is adequate for screening purposes.
The local laboratory will perform all tests found in Table 9.a, as per the Schedule of Study 
Procedures (Appendix A). The results of laboratory tests will be returned to the investigator, who 
is responsible for reviewing and filing these results.
Any clinically significant laboratory result will be captured as an AE as per the NCI CTCAE v5.0.
Treatment with study drug should be discontinued in subjects who develop liver test elevation as 
described in Section 10.1.6.4.
9.1.13
Contraception and Pregnancy Avoidance Procedure
Animal studies for TAK-954 have demonstrated embryotoxicity and there is a lack of adequate 
reproductive toxicity data in humans. 
Given that TAK-954 did not exhibit genotoxic potential in the standard battery of genotoxicity 
assays and the terminal disposition phase half-life of TAK-954, the duration of contraception for 
30 days after the last dose is considered acceptable. This is in line with the Clinical Trials 
Facilitation Group “Recommendations related to contraception and pregnancy testing in clinical 
trials.”
Females of reproductive potential, as well as fertile men and their partners who are female of 
reproductive potential, must agree to abstain from sexual intercourse or to use a highly effective 
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form of contraception from the time of giving informed consent, during the study, and for 30 days 
(females and males) following the last dose of study drug. A highly effective form of contraception 
is defined as follows:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation:
–
Oral.
–
Injectable.
–
Implantable.

Intrauterine device.

Intrauterine hormone-releasing system.

Bilateral tubal occlusion.

Vasectomized partner.

Sexual abstinence.
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 postmenopausal 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. 
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.
9.1.14
Pregnancy
If any subject is confirmed to be pregnant during the study, TAK-954 should be immediately 
discontinued. In addition, any pregnancies in the partner of a male subject during the study or for 
30 days after the last dose should also be recorded following authorization from the subject’s 
partner. A pregnancy notification form should be submitted within 24 hours of learning of the 
pregnancy to the contact listed in Section 1.0.
If the female subject and/or female partner of a male subject agree to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
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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.
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. The study follow-up visits should also 
be completed. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted. 
9.1.15
ECG Procedure
ECG assessments collected as SOC within 21 days of randomization may be used for study 
screening purposes. If an ECG is collected as SOC on the day of surgery but prior to informed 
consent, it may be used for screening/baseline purposes as long as the results are assessed for 
eligibility prior to randomization. A standard 12-lead ECG will be performed as follows:

Screening (Days -21 to 1) (to be reviewed by a medically qualified person). 

Day 1: prior to and at the end of the 60-minute IV infusion (+20 minutes).

Day 2: At the end of the 60-minute IV infusion (+20 minutes) and approximately 2 hours (+20 
minutes) after the start of the 60-minute infusion.

Days 4, 6, 8, and 10: at the end of the 60-minute IV infusion (+20 minutes) on every other day 
of treatment.

Early termination (as applicable).
Subjects should have rested in a supine or semisupine position for at least 5 minutes before ECG. 
The same position (either supine or semisupine) should be used for the same individual throughout 
the study.
When ECG, vital signs, and blood draw coincide at the same nominal time point, the sequence of 
procedures will be safety ECG, vital signs assessment, and blood draw.
In addition, a 12-lead ECG will be performed if a subject develops symptoms suggestive of CV 
origin (eg, dizziness, chest pain, lightheadedness, chest pain, chest heaviness, palpitations, 
shortness of breath, tachycardia). 
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. The time that a 12-lead 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, QRS, and QT interval. The sponsor will derive QTcF. Heart-rate corrected 
QT interval will be calculated using Fridericia formula (QTcF = QT/RR1/3). This same formula 
should be used for assessing eligibility. 
New onset or changes in ECG findings (compared with baseline Day 1 preinfusion values) are 
considered to be AEs only if they are judged to be clinically significant as per CTCAE v5.0 (ie, if 
some action or intervention is required or if the investigator judges the change to be beyond the 
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range of normal physiologic fluctuation). If abnormal ECG findings are the result of pathology for 
which there is an overall diagnosis, the diagnosis should be reported appropriately as an AE 
(Section 10.1).
9.1.16
Biomarker Sample Collection
Biomarkers samples will be taken for exploratory analysis as shown in Table 9.b.
Biomarkers associated with inflammation, nausea, or intestinal motility including but not limited 
to cortisol, IL-6, IL-10, MCP-1, and CRP will be measured depending on assay feasibility. 
Subjects will have serum biomarker samples collected prior to and at the end of the infusion 
(+10 minutes) and after surgery on Day 1; on Day 2, prior to and at 4 hours (+10 minutes) after the 
start of the infusion; on Day 3 up to Day 10, a predose sample will be obtained every other day. 
Sample collection instructions for circulating biomarkers will be explained in detail in the 
laboratory manual to be provided to the site. The samples will be stored at site/commercial vendor, 
and analyzed as needed.
9.1.17
PK Sample Collection
9.1.17.1
Collection of Plasma for PK Sampling
Subjects will have PK samples collected as follows:

Day 1: Collect 1 sample prior (within 30 minutes) to the start of the infusion, 1 sample at the 
end of the 60-minute infusion (+10 minutes), and another sample within the 1- to 3-hour 
window after the surgery, for a total of 3 samples. 

Day 2: Collect 1 sample prior (within 30 minutes) to the start of the infusion, 1 sample at the 
end of the 60-minute infusion (+10 minutes), and an additional sample within the 3- to 5-hour 
window after the end of the infusion, for a total of 3 samples.

Day 3 up to Day 10 while on study drug: a trough (predose, within 30 minutes of the start of the 
infusion) sample obtained every other day starting on Day 3.
Times indicated are relative to the start of the infusion. It is important that the date and time of each 
sample collection be accurately recorded on the eCRF. The date and time of start and end of 
infusion should also be accurately recorded on the eCRF. All blood samples, except the sample 
collected at the end of infusion, collected outside the exact nominal time windows will not be 
captured as protocol deviations as long as the date and exact time of the sample collection is noted 
on the source document and eCRF. Placebo PK samples will not be analyzed; therefore, the 
randomization code will be sent to the analyzing laboratory. If indicated, collected TAK-954 
samples may also be assayed in an exploratory manner for metabolites if deemed necessary for 
interpretation of the data and these data will be reported in PK listings only.
When ECG, vital signs, and blood draw coincide at the same nominal time point, the sequence of 
procedures will be safety ECG, vital signs assessment, and blood draw.
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9.1.18
Primary Specimen Collection
Primary specimen collections are provided in Table 9.b.
Table 9.b
Primary Specimen Collection
Specimen Name
Primary 
Specimen
Description of Intended Use
Sample Collection
Serum sample for circulating biomarkers
Serum
Biomarker measurement
Mandatory
Plasma sample for TAK-954 PK
Plasma
PK measurements
Mandatory
Abbreviations: PK, pharmacokinetic.
9.1.19
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is withdrawn at the screening visit after signing the informed consent, the 
investigator should complete the required screening eCRFs. The IRT should be contacted as a 
notification of screen failure. No follow-up visits are expected. 
The primary reason for screen failure is recorded in the subject source documents and eCRF using 
the following categories:

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 reason.

Other (specify reason).
Subject identification numbers assigned to subjects who fail screening should not be reused. 
Subjects may be rescreened 1 time and will be given a new subject ID. 
9.1.20
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.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
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9.1.21
Quality of Life Assessment
Quality of life will be assessed by subjects completing the following questionnaires at baseline, 
last day of treatment, and the follow-up visit at 14 days (±4 days) post last dose:

SF-12.

EQ-5D.
At discharge, a printed copy of SF-12 and EQ-5D (with pre-addressed envelopes) will be provided 
to subjects as part of their discharge packages. If the Day 14 visit is done via phone follow-up, the 
study coordinator will remind subjects to complete the quality of life scales on the same day as the 
follow-up phone call and completed questionnaires will be mailed to the clinic.
9.2
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).
9.2.1
Post Study Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required.
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment SAEs
After informed consent, but before initiation of study drugs, only SAEs caused by a 
protocol-mandated intervention will be collected (eg, SAEs related to invasive procedures).
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 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 AEs.)

Necessitate therapeutic intervention.
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
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.
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 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 an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be 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 are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. If the subject experiences 
a worsening or complication of such a concurrent medical condition, the worsening or 
complication should be recorded appropriately 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 AE if the condition becomes more 
frequent, serious, or severe in nature. 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 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…”).
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Worsening of AEs:

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:

If the subject experiences changes in intensity of an AE, 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 AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered 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:
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.
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5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT based on the opinion of either the investigator or 
sponsor 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.
10.1.5
Severity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to CTCAE v5.0. AEs not listed by the NCI CTCAE will be graded displayed in 
Table 10.a.
Table 10.a
NCI CTCAE
Grade
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.
2
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL a.
3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care ADL.
4
Life-threatening consequences; urgent intervention indicated.
5
Fatal AE; an event that results in the death of the subject.
Abbreviations: ADL: activities of daily living; AE, adverse event; NCICAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events.
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.
10.1.6
Management of Specific AEs
10.1.6.1
CV Disorders
CV Events:
Subjects with clinically significant ECG abnormalities indicative of acute cardiac instability or 
acute myocardial ischemia or infarction, as determined by the investigator at screening will be 
excluded from the study. 
Suspected CV events that include ischemic heart disease, cerebrovascular accident (eg, transient 
ischemic attack and stroke), venous or arterial thromboembolic events, and heart failure, should be 
reported as an AESI to the sponsor within 24 hours irrespective of the seriousness. These events 
will be adjudicated by a cardiovascular endpoint committee (CEC).
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QT prolongation
Subjects with >5 beats of nonsustained VT at a rate >120 bpm or have QTcF ≥450 msec or other 
factors that increase the risk of QT prolongation or arrhythmic events at screening will be excluded 
from the study. Subjects with bundle branch block and a prolonged QTcF should be reviewed by a 
cardiologist for potential inclusion.
Any QT prolongation event assessed as Grade 2 or worse (QTcF longer than 480 msec), 
irrespective of the seriousness, should be reported as an AESI to the sponsor within 24 hours and 
managed according to the guidelines below. 
Table 10.b
Management of QT Prolongation by NCI CTCAE Grade
NCI CTCAE Grade
Management
Grade 2 
(QTcF a >480 and ≤500 msec) 
Levels of electrolytes (potassium, calcium, and magnesium) should be 
checked and supplementation given to correct any values outside the 
normal range.
Concomitant therapies should be reviewed and adjusted as appropriate 
for medications with known QT prolonging effects.
If no other cause is identified and the investigator believes it is 
appropriate, particularly if QTcF remains elevated (after the above 
measures have been implemented, or as determined by the 
investigator), study treatment may be interrupted for 1 dose for up to 2 
days, and an ECG should be rechecked regularly. If QTcF remains 
elevated, study treatment will be discontinued.
If QTcF has recovered or improved <450 msec and the investigator 
believes it is safe to do so, rechallenge with study treatment should be 
considered after discussion with the medical monitor.

ECGs should be conducted at least weekly (eg, at every scheduled 
visit) for 2 weeks following QTcF reduction ≤480 msec.

Discontinue treatment with study drug if the subject develops a 
second episode of Grade 2 QT prolongation.
Grade 3 
(QTcF a >500 msec) or >60 msec change 
from baseline
OR
Grade 4 
Torsades de pointes or polymorphic VT or 
signs/symptoms of serious arrhythmia 
Subjects should have continuous cardiac monitoring and be discharged 
only after review by a cardiologist. 

Treatment with study treatment should be permanently 
discontinued. 
Abbreviations: ECG, electrocardiogram; NCI CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; QTcF, QT interval with Fridericia correction method; VT, ventricular tachycardia.
a Heart rate-corrected QT interval will be calculated using Fridericia’s formula (QTcF=QT/RR1/3).
AV Dissociation/Heart Block
Patients with AV block other than first degree heart block will be excluded from the study.
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Treatment with study drug should be discontinued with the occurrence of any second- or 
third-degree heart block and these events should be reported to the sponsor as AESI within 24 
hours.
Treatments with study drug may be continued in second-degree heart block Mobitz I (Wenckebach) 
after medical monitor review.
SVT
Any SVT assessed as Grade 2 or worse irrespective of the seriousness should be reported as an 
AESI to the sponsor within 24 hours and managed according to the following guidelines.
Table 10.c
Management of SVT by NCI CTCAE Grade
NCI CTCAE Grade
Management
Grade 2: Symptomatic; nonurgent medical 
intervention indicated
Or G3: Urgent medical intervention 
indicated
Rule out other etiology such as pain, hypovolemia, or pyrexia.
If no other cause is found and SVT is persistent: study drug should be 
interrupted for 1 to 2 days.
Treatment can be restarted if the patient is hemodynamically stable 
with careful monitoring.
G4: Life-threatening consequences; urgent 
intervention indicated
Study drug should be discontinued and the patient managed as per local 
guidelines. 
Abbreviations: NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; SVT, 
supraventricular tachycardia.
Hypotension/Orthostatic Hypotension
If the subject has orthostatic hypotension prior to dosing, the treatment should be delayed and the 
case should be discussed with the medical monitor. 
If any subject develops Grade 3 hypotension or orthostatic hypotension, the medical monitor 
should be contacted and the hypotensive event should be investigated and managed as per 
institutional guidelines.
For Grade 4 hypotension, treatment with study drug should be discontinued. 
10.1.6.2
Serotonin Syndrome
Neurological examinations looking for hypertonicity, reflexes, and clonus will be performed at 
screening and during treatment with study drug as per the Schedule of Study Procedures 
(Appendix A). 
Treatment with study drug should be discontinued if a subject develops any of the following 
clinical features (Hunter’s criteria):

Spontaneous clonus.

Inducible clonus PLUS agitation or diaphoresis.
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
Ocular clonus PLUS agitation or diaphoresis.

Tremor PLUS hyperreflexia.

Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus.
In case of a suspected serotonin syndrome, treatment with TAK-954 and/or other potential 
serotoninergic drugs will be immediately interrupted and other supportive and therapeutic 
measures will be initiated as clinically indicated. Any suspected case of serotonin syndrome will 
be reported to the sponsor as a serious AESI within 24 hours.
10.1.6.3
Diarrhea
AEs of diarrhea (new onset or change from baseline) should be investigated for underlying 
etiology and graded for severity as per the NCI CTCAE grading system, as follows:

Grade 1: Increase of <4 stools per day over baseline; mild increase in ostomy output compared 
to baseline.

Grade 2: Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output 
compared to baseline.

Grade 3: Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self-care of activities of daily 
living. 

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death.
Diarrhea Grade 3 and above should be reported as AESI to the sponsor within 24 hours.
10.1.6.4
Abnormal Liver Tests
Treatment with study drug should be discontinued in subjects who develop ALT and/or 
AST >3 × ULN concurrently with total bilirubin >2 × ULN while on treatment with study drug. 
These findings should be reported to the sponsor as a serious AESI. The investigator must contact 
the medical monitor for discussion of the relevant subject details and possible alternative 
etiologies such as acute viral hepatitis, other acute liver disease, or medical history/concurrent 
medical conditions. In addition, the investigator should contact the medical monitor for any 
increase in liver tests without clear etiology.
10.1.6.5
AESI
An AESI (serious or non-serious) is 1 of scientific and medical concern specific to the compound 
or program, for which ongoing monitoring and these events must be reported within 24 hours of 
awareness to the sponsor.
The following events will be reported as AESI:
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
Suspected CV events (ischemic heart disease, cerebrovascular accident [eg, transient ischemic 
attack and stroke], venous or arterial thromboembolic events, and heart failure).

QT prolongation G2 or above.

2nd or 3rd degree heart block.

SVT G2 or above with heart rate over 130 bpm.

Suspected serotonin syndrome.

Diarrhea Grade 3 or higher.

Liver test elevations as defined in Section 10.1.6.4.
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 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/SAE 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/SAE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11 Frequency 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
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10.1.12
Action Concerning Study Drug 

Dose interrupted – the dose was interrupted due to the particular AE. Subjects will discontinue 
treatment with study drug if the interruption is for 2 or more doses.

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.
10.1.13
Outcome

Recovered/resolved – Subject returned to first assessment status with respect to the AE.

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 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 state remaining “Not recovered/not 
resolved.”

Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a CV accident but with some persisting 
paresis).

Fatal – the AEs which are considered as the cause of death. 

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of SAEs caused by a protocol-mandated intervention 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. 
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Collection of AEs and SAEs (treatment-emergent) will commence from the time that the subject is 
first administered study drug (Day 1). Routine collection of AEs and SAEs will continue until the 
final follow-up visit (90 days post last dose).
10.2.1.2
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. 
All subjects experiencing AEs or SAEs, 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 AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:
1. Event term.
2. Start and stop date.
3. Frequency.
4. Severity as per NCI CTCAE.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drugs (related or not related).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9. Seriousness.
10.2.1.3
AESI
AESI have to be recorded as AEs in the eCRF. An evaluation form along with all other required 
documentation must be submitted to the sponsor.
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:
As soon as an SAE is entered into the electronic data capture system, an alert is sent to the attention 
of the contact listed in Section 1.1.
The information should be completed as fully as possible but contain, at a minimum:
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A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE eCRF should be transmitted within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE form should be completed and reported to the 
attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
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 or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted 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 trial. The study site also 
will forward a copy of all expedited reports to his or her IRB or IEC.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Independent CEC
An independent CEC consisting of 2 CV experts and 1 neurologist will review and adjudicate all 
suspected CV events in a blinded fashion to determine if the reported event meets the criteria for 
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major adverse cardiac event. Details of the independent CEC, including meeting frequency, will 
be captured in a charter prior to the start of the trial.
11.2
Internal Monitoring Committee
An IMC within Takeda composed of a senior clinician, a senior statistician, and a senior 
pharmacovigilance physician not involved in the study will perform ongoing reviews of the 
serious AEs, conduct periodic scheduled reviews of safety, and conduct reviews of IA results. The 
IMC is responsible for making recommendations for changes to the study after the IA, if 
appropriate. 
Details of the IMC, including meeting frequency, will be captured in a charter prior to the start of 
the study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent 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 the sponsor’s 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must 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.
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eCRFs will be reviewed for completeness and acceptability during periodic monitoring 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), 
and detailed records of drug disposition to enable evaluations or audits from regulatory authorities, 
the sponsor or its designees. Any source documentation printed on degradable thermal sensitive 
paper should be photocopied by the site and filed with the original in the subject’s chart to ensure 
long term legibility. Furthermore, International Conference on Harmonisation (ICH) E6 Section 
4.9.5 requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at 
least 2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the 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.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) 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.
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods.
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13.1.1
Analysis Sets
The full analysis set (FAS) will include all subjects who were randomized and received at least 
1 dose of study drug, and have at least 1 postbaseline value for assessment of efficacy. In FAS 
efficacy summaries, subjects will be analyzed by the treatment to which they were randomized. 
The per-protocol set (PPS) will include all FAS subjects who had no major protocol deviation that 
could confound the interpretation of the primary analyses based on the FAS. The major protocol 
deviations that lead to a subject’s exclusion from the FAS to form the PPS will be specified in the 
SAP. The PPS will be used to perform sensitivity analysis for the efficacy endpoints.
The safety set will include all subjects who were randomized and received at least 1 dose of 
double-blind study medication. In safety summaries, subjects will be analyzed according to the 
treatment they received.
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
Efficacy Analysis
The primary efficacy endpoint is time from the end of surgery to resolution of upper and lower GI 
function (ie, time to first tolerance of solid food [defined as first occurrence of no vomiting or no 
clinically significant nausea for 1 calendar day after a solid meal] and first spontaneous bowel 
movement, whichever occurs later) up to Day 10 postsurgery. 
The primary endpoint will be analyzed using the Cox proportional hazard model with treatment 
group as a single covariate, with Efron’s method of tie handling, stratified by randomization 
stratification factor. Hazard ratios between TAK-954 doses/regimens and placebo and their 90% 
CIs based on the Cox model will be presented. P-values for the comparisons of TAK-954 
doses/regimens and placebo will be calculated using Wald chi-square test based on the Cox model 
and presented. Median time to resolution of upper and lower GI function will be estimated by 
Kaplan-Meier survival analysis. The hazard ratios and median time differences between TAK-954 
doses/regimens and placebo will be used to express the magnitude of treatment effects. The 
statistical tests will be 1-sided comparing TAK-954 doses/regimens to placebo. As a sensitivity 
analysis, the primary endpoint will be analyzed using the same method above based on PPS. 
In the final analyses of efficacy endpoints, for the 2 discontinued treatment arms, only the 
summary statistics (n, mean, SD, median, minimum, and maximum for continuous endpoints; 
number and percentage of subjects for categorical data; the number and percentages of events and 
censoring, median, minimum, and maximum for time to event endpoint) will be provided; for the 
remaining treatment groups after IA, the inferential statistics (point estimates of interest and 90% 
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CIs and 1-sided p-values) for each treatment group and the TAK-954 doses/regimens in 
comparison with placebo will be provide along with summary statistics.
The secondary endpoints time to tolerance of solid food from the end of surgery, time to first 
spontaneous bowel movement from the end of surgery, time from the end of surgery until ready for 
discharge, time from the end of surgery until the discharge order is written, time from the end of 
surgery to discharge from hospital, and time from the end of surgery to first flatus will be analyzed 
using similar statistical methods described for the primary efficacy analysis. 
The comparisons of TAK-954 dose levels and placebo in percent of subjects with POGD ≥5 days 
and the percent of subjects requiring insertion of NG tube postsurgery will be based on the 
Miettinen and Nurminen’s method stratified by randomization stratification factor for risk 
difference.
13.1.4
PK Analysis
No formal noncompartmental PK analyses will be performed on concentration-time data. The 
observed plasma concentrations of TAK-954 will be summarized by dose/regimen at study 
scheduled day/time point where appropriate. Individual concentration-time data for TAK-954 and 
its metabolites will be included in listings. 
A population PK analysis may be conducted and a more detailed description of these analyses will 
be given in a separate analysis plan. The results from these analyses will not be included in the 
clinical study report and will be a standalone report.
13.1.5
Safety Analysis
AEs will be summarized using the safety analysis set. 
All AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class. The definition of treatment-emergent AEs will be provided in the SAP. AEs 
will be coded using MedDRA and will be summarized by system organ class and preferred term in 
the core treatment period and entire study.
AEs that were reported more than once by a subject during the same period will be counted only 
once for that subject and period at the maximum severity.
Clinical Evaluations:
Absolute values and changes from screening/baseline in clinical safety laboratory tests, vital signs, 
ECG parameters, and weight will be summarized for each treatment group using descriptive 
summary statistics. Values outside normal ranges and potentially clinically significant values will 
be flagged and tabulated.
13.2
IA and Criteria for Early Termination
The first IA will be conducted after approximately 125 subjects (25 per arm) have completed or 
withdrawn from the study. The second IA is removed. Following the IA, bayesian approach for 
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decision making will be implemented for the potential study modification including futility, 
regimen decision, and sample size adjustment. 
The IMC will review the IA 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.
13.3
Determination of Sample Size
Assuming 80% of subjects will have resolution of POGD at the end of study in the placebo group 
and 92.5% of subjects will have resolution of POGD at the end of study in the active TAK-954 
doses, a total of approximately 300 subjects (100 per treatment group) will provide 80% power 
with a 0.05 2-sided significance level under Protocol Amendment 4.
In order to mitigate the statistical, clinical, and operational risks to this study in light of the 
COVID-19 pandemic, the probability of success of the study is re-estimated by blinded 
assessments using efficacy assumptions of Protocol Amendment 4. Specifically, by the removal of 
the second IA per this amendment and changing the statistical significance level from 2-sided 5% 
to 1-sided 5%, the resulting sample size is an overall total of 50 subjects for each remaining arm 
(Figure 6.b). Under these revised assumptions and the dropping of 2 arms, an overall total of 
approximately 180 subjects for the study will provide approximately 80% probability, for at least 1 
remaining TAK-954 treatment arm, that TAK-954 is superior to placebo in time to resolution of 
upper and lower GI function at a 1-sided 5% significance level for the final analysis.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits will be made periodically during the study to ensure that all aspects of the 
protocol are followed. Monitoring may be done remotely where allowed by local regulations and 
ethics approvals. Source documents will be reviewed for verification of data recorded on the 
eCRFs. Source documents are defined as original documents, data, and records. The investigator 
and the study site guarantee access to source documents by the sponsor or its designee (contract 
research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 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 (if separate from the informed consent 
form), 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.
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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 or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
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 or EC, 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. 
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 study drug 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, 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 and study sites guarantee access for quality assurance auditors to all study 
documents as described in Section 14.1.
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 and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
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Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will 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 or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. 
All IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject reimbursements should not exert undue influence for participation. Payments to subjects 
must be approved by the IRB or IEC 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 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable)
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
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The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC.
The subject 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 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 at the time of consent and prior to the subject entering into the 
study. The subject 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.
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 in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
Subjects who consented and provided a sample for DNA analysis can withdraw their consent and 
request disposal of a stored sample at any time prior to analysis.
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 trial 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 and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
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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.
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
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 Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
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.
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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.
16.0
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13. Kenward H, Elliott J, Lee T, Pelligand L. Anti-nausea effects and pharmacokinetics of 
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postoperative ileus. Ann Surg 2014;259(4):708-14.
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Appendix A
Schedule of Study Procedures
Days
-21 to 
1 a
Baseline/Day 1 
(Preinfusion) b
Day 1 
(Postinfusion)
Day 2 
to up 
Day 10
Early 
Termination 
(ET)
Days 16 to 24 
Interim 
Follow-up 
(14 Days [±4 
Days] Post 
Last Dose) c
Days 32 to 40 
Follow-up (30 days [±3 
days] Post Last Dose) 
(Phone Call)
Days 92 to 100 
(90 days [±7 days]) 
Post Last Dose
Final Follow-up 
(Phone Call)
Informed consent d
X
Inclusion/exclusion 
criteria
X
X e
Demographics and medical 
history
X
X
Medication history
X
X
Physical examination 
(including neurology 
examination) f
X
X
X
X
X
Height, weight, and BMI 
X
Vital signs g
X
X
X
X
X
Clinical assessment 
X
X
X
Concurrent medical 
procedures
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
ERP assessment
X
X h
Clinical laboratory 
evaluations i
X
X
X
X
Serum or urine pregnancy 
test (hCG) j
X
X
X
12-lead ECG k
X
X
X
X
X
Study drug dosing l
X
X
Surgery m
X
Plasma sample for 
TAK-954 PK n
X
X
X
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Days
-21 to 
1 a
Baseline/Day 1 
(Preinfusion) b
Day 1 
(Postinfusion)
Day 2 
to up 
Day 10
Early 
Termination 
(ET)
Days 16 to 24 
Interim 
Follow-up 
(14 Days [±4 
Days] Post 
Last Dose) c
Days 32 to 40 
Follow-up (30 days [±3 
days] Post Last Dose) 
(Phone Call)
Days 92 to 100 
(90 days [±7 days]) 
Post Last Dose
Final Follow-up 
(Phone Call)
Serum sample for 
circulating biomarkers o
X
X
X
Ready for discharge p
X
Discharge papers written
X
Discharge from hospital q
X
EQ-5D r
X
X
X
SF-12 r
X
X
X
AE assessment s
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; BMI, body mass index; COVID-19, coronavirus disease 2019; ECG, electrocardiogram; EQ-5D, EuroQol 5-dimensional questionnaire; ERP, 
enhanced recovery pathway; GI, gastrointestinal; HbA1c, glycosylated hemoglobin; PK, pharmacokinetics; SF-12, 12-Item Short Form Health Survey; SOC, standard of care.
a All screening procedures need to be reviewed before randomization if done on Day 1. These screening procedures may be used as baseline parameters on Day 1.
b The day of first study drug administration for the treatment period is Day 1. Baseline evaluations are defined as the assessment before first dose of study drug.
c During the COVID-19 public health emergency, every attempt should be made to perform the follow-up visit at 14 days post last dose in clinic however, it may be conducted at the 
clinic or via phone call (eg, collection of AEs, concomitant medications, and monitoring) to extend flexibility to study subjects. In the case of a phone call follow-up, physical 
examination (including neurology examination), vital signs, or pregnancy test would not be collected; however, AEs will be assessed, including a safety check on any emerging 
clinical sign or symptoms. Subjects may be requested to return to the site for further safety assessment, due to reported AEs, at the investigator’s discretion. The type of visit (whether 
clinic visit or phone call) must be recorded in the study records.
d Informed consent will be signed before any study-specific procedures are performed. Informed consent may be performed in clinic or remotely using electronic signature where 
allowed by site institutional review boards/ethics committees.
e Excluded medications should be reassessed during the 24 hours prior to surgery.
f Physical examination includes a neurology examination. A targeted neurological examination looking for hypertonicity, reflexes, and clonus will be performed by medically 
qualified personnel at screening, baseline (preinfusion on Day 1), on Days 2 and 5, on the last day of treatment, at the early termination visit (as applicable), and at the safety follow-up 
visit (14 days post last dose). Physical examinations collected as SOC within 21 days of randomization may be used for study screening purposes. If physical examinations are 
collected as SOC on the day of surgery but before informed consent, they may be used for screening/baseline purposes as long as the results are assessed for eligibility before 
randomization.
g Vital signs will include blood pressure (systolic and diastolic) and pulse (beats per minute). Vital signs collected as SOC within 21 days of randomization may be used for study 
screening purposes. If vital signs are collected as SOC on the day of surgery but before informed consent, they may be used for screening/baseline purposes as long as the results are 
assessed for eligibility before randomization. Vital signs will be collected at the following time points: screening, presurgery before and at the end of infusion on Day 1, on Days 2 to 
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10 (ie, at the end of infusion in the morning and in the evening), and at the safety follow-up visit (on 14 days post last dose visit). Vital signs on day of surgery will be monitored 
according to SOC. Clinically abnormal vital signs will be captured as an AE as per NCI CTCAE v5.0. Subjects should have rested for at least 5 minutes before vital signs are assessed. 
When ECG, vital signs, and blood draw coincide at the same nominal time point, the sequence of procedures will be safety ECG, vital signs assessment, and blood draw.
h Assessment of ERP will be during the perioperative period on Day 1 and 2 only.
i Laboratory samples will be collected at screening, preinfusion Day 1 (Baseline) (note: it is not required that Day 1 laboratory assessments are reviewed before study drug 
administration) and Day 2. Results of clinical laboratory assessments collected as SOC within 21 days of randomization may be used for study screening purposes. If laboratory 
assessments are collected as SOC on the day of surgery but before informed consent, they may be used for screening/baseline purposes as long as the results are assessed for eligibility 
before randomization. In addition, liver test parameters (ie, ALT, AST, total bilirubin, alkaline phosphatase) will be tested on the last day of study dosing and early termination (as 
applicable). Clinical laboratory samples will be collected as per SOC and will not be duplicated. HbA1c to be collected at screening only (or collected as SOC within 30 days of 
informed consent may be used for screening purposes). Any clinically significant laboratory result will be captured as an AE as per NCI CTCAE v5.0.
j For women of childbearing potential. Beta hCG will be collected at screening, early termination (if applicable), and the follow-up visit (ie, 14 days post last dose).
k ECGs will be collected at screening; prior to and at the end of the infusion (+20 minutes) on Day 1; at the end of the 60-minute IV infusion (+20 minutes) and approximately 2 hours 
(+20 minutes) after the start of the 60-minute infusion on Day 2; at the end of the infusion (+20 minutes) on every other day of treatment (Days 4, 6, 8, and 10), and early termination 
(as applicable). Subjects should have rested in a supine or semisupine position for at least 5 minutes before ECG assessment. The same position (either supine or semisupine) should 
be used for the same individual throughout the study. ECG assessments collected as SOC within 21 days of randomization may be used for study screening purposes. If an ECG is 
collected as SOC on the day of surgery but before informed consent, it may be used for screening/baseline purposes as long as the results are assessed for eligibility before 
randomization. When ECG, vital signs, and blood draw coincide at the same nominal time point, the sequence of procedures will be safety ECG, vital signs assessment, and blood 
draw.
l On Day 1, the completion of the infusion should occur within 3 hours of the start of the surgery (induction of anesthesia). Subsequent doses (Days 2 to 10, if required) should be 
approximately 24 hours (±5 hours) from the start of the prior infusion. If a subsequent dose cannot be administered during this window, it should be skipped.
m The start and stop times of the surgery must be recorded. The start time of surgery is the start of general anesthesia.
n Subjects will have PK samples collected as follows: Day 1: Collect 1 sample prior (within 30 minutes) to the start of the infusion, 1 sample at the end of the 60-minute infusion (+10 
minutes), and another sample within the 1- to 3-hour window after the surgery, for a total of 3 samples. Day 2: Collect 1 sample prior (within 30 minutes) to the start of the infusion, 
1 sample at the end of the 60-minute infusion (+10 minutes), and an additional sample within the 3- to 5-hour window after the end of the infusion, for a total of 3 samples; Day 3 up 
to Day 10 while on study drug: a trough (predose, within 30 minutes of the start of the infusion) sample obtained every other day starting on Day 3. For the PK samples that correlate 
with the end of study drug infusion, the sample should always be collected from the arm opposite to the arm in which study drug is infused. When ECG, vital signs, and blood draw 
coincide at the same nominal time point, the sequence of procedures will be safety ECG, vital signs assessment, and blood draw.
o Subjects will have serum biomarker samples collected prior to and at the end of the infusion (+10 minutes) on Day 1 and after surgery; on Day 2, prior to and at 4 hours (+10 minutes) 
after the start of the infusion; on Day 3 up to Day 10, and a predose sample will be obtained every other day.
p Ready for discharge is defined as the time when the subject presents effective intestinal transit (spontaneous bowel movement), tolerates solids without clinically significant nausea 
and vomiting for 1 calendar day, has satisfactory pain control with oral analgesics, and is medically stable/free of complications. 
q Discharge cannot occur prior to the occurrence of the primary endpoints. If a subject meets the primary endpoint after midnight, discharge procedures can be completed the next day. 
This would not be considered a protocol deviation. If a subject meets the primary endpoint in the morning and is discharged later that day, this is considered a minor protocol 
deviation.
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r EQ-5D and SF-12 questionnaires will be conducted at baseline, last day of treatment, and at the Day 14 post last dose follow-up visit. At discharge, printed copy of SF-12 and EQ-5D 
(with pre-addressed envelopes), will be provided to subjects as part of their discharge packages. If the Day 14 visit is done via phone follow-up, the study coordinator will remind 
subjects to complete the quality of life scales on the same day as the follow-up phone call and completed questionnaires will be mailed to the clinic.
s After informed consent, but before initiation of study drugs, only SAEs caused by a protocol-mandated intervention will be collected (eg, SAEs related to invasive procedures). All 
AEs and SAEs (treatment-emergent) will be collected from study drug start until 90 days post last dose. Serious and nonserious CV events (suspected ischemic heart disease, 
cerebrovascular accident [eg, transient ischemic attack and stroke], venous or arterial thromboembolic events, or heart failure), SVT/arrhythmias and death will be collected.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff 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/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined, 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/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject.
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.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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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 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 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/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
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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 30 days after the last 
dose. 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 30 days after
the 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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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 and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study 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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Appendix E
Protocol History
Date
Amendment Number
Amendment Type
Region
23 March 2021
Amendment 5
Substantial
Global
09 July 2019
Amendment 4
Substantial
Global
13 May 2019
Amendment 3
Substantial
Local (Germany)
23 April 2019
Amendment 2
Nonsubstantial
Local (Belgium)
19 December 2018
Amendment 1
Not applicable
Global
15 October 2018
Initial protocol
Not applicable
Global
Rationale for Amendment 4
The primary reason for this amendment is to produce 1 common international protocol by 
incorporating individual country amendments (Germany’s Bundesinstitut für Arzneimittel und 
Medizinprodukte [BfArM] and Belgium’s Federal Agency for Medicines and Health Products) 
containing responses to their regulatory reviews. In addition, the amendment contains changes to 
address operational issues and an updated list of prohibited medicines as a consequence of new 
data supporting the absence of direct evidence suggesting a relationship between selective 5-HT4
agonist and serotonin syndrome.
Changes in Amendment 4
1. Clarification of the end of the surgery.
2. Correction of the collection of a peak nausea severity score.
3. Clarification of the maximum dose that will be used for this study.
4. Addition of the justification for a maximum dose of 1.0 mg TAK-954.
5. Added definition for the end of the study.
6. Deleted “subject’s legally acceptable representative”.
7. Clarification of who can review an electrocardiogram (ECG) for inclusion into the study.
8. Revised the timeframe for excluded medications.
9. Clarification of laxative use.
10. Removal of medications associated with serotonin syndrome.
11. Clarification of drug dosing in relation to surgery delays.
12. Clarification of the use of the interactive response technology (IRT).
13. Clarification of the procedure for clinically significant physical examination changes.
14. Addition of the collection of approximate length of bowel removed during surgery.
15. Clarification of the clinical assessments.
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16. Revised highly effective forms of contraception.
17. Clarification of ECG procedures.
18. Clarification of the quality of life assessment.
19. Clarification of specific adverse events (AEs) related to cardiovascular (CV) events. 
20. Correction of the management of QT prolongation.
21. Clarification of the procedure for suspected serotonin syndrome.
22. Correction of action concerning study drug.
23. Correction of the members of the internal monitoring committee (IMC).
24. Correction of the analysis of the primary endpoint.
25. Addition of a pregnancy test at the Days 16 to 24 follow-up visit.
26. Correction and clarification of laboratory sample collection.
27. Clarification of pharmacokinetic (PK) sample collection.
28. Correction of plasma and serum biomarker sample collection.
29. Correction of ERP assessments.
Rationale for Amendment 3
The primary reason for this amendment is in response to the Bundesinstitut für Arzneimittel und 
Medizinprodukte responses.
Changes in Amendment 3:
1. Added definition for the end of the study.
2. Deleted “subject’s legally acceptable representative”.
3. Revised the timeframe for excluded medications.
4. Revised highly effective forms of contraception.
5. Added a pregnancy test at the Days 16 to 24 follow-up visit.
Rationale for Amendment 2
The primary reason for this amendment is in response to the Federal Agency for Medicines and 
Health Products.
Changes in Amendment 2
1. Clarification of the maximum dose that will be used for this study.
2. Addition of the justification for a maximum dose of 1.0 mg TAK-954.
3. Addition of a pregnancy test at the Days 16 to 24 follow-up visit.
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Rationale for Amendment 1
The primary reason for this amendment is clarification following initial discussion with 
investigators.
Changes in Amendment 1
1. Revision and addition of exploratory objectives.
2. Clarification of primary endpoint.
3. Addition and clarification of secondary endpoints.
4. Addition and clarification of exploratory endpoints.
5. Deletion and clarification of core enhanced recovery pathway (ERP).
6. Removal of subject daily diary and clarification of bowel movement.
7. Revision of exclusion criteria regarding glycosolated hemoglobin requirements and addition of 
exclusion criteria regarding radiation.
8. Revised and added criterion for discontinuation or withdrawal of a subject regarding study 
drug dosing.
9. Additional instructions related to timing of dosing and the surgery.
10. Addition and clarification of vital sign measurements.
11. Revision of POGD assessment.
12. Added section for documentation of concurrent medical procedures.
13. Clarification of concomitant medications.
14. Clarification of concurrent medical conditions.
15. Revised pregnancy test to allow for serum or urine and added glycosylated hemoglobin 
(HbA1c) to the clinical laboratory table.
16. Clarification of ECG procedures.
17. Clarification of PK sampling.
18. Added a quality of life assessment at hospital discharge.
19. Correction of SAE or AESI reporting to the safety database.
20. Addition of Baseline column to Schedule of Assessments table and corrections throughout. 
21. Correction of the documentation of clinically significant changes for physical examinations.
22. Added laxatives to the excluded medications list.
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
NCT Number: 
Study Title: 
Study Number: 
NCT03827655 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose 
Ranging Study to Evaluate the Efficacy and Safety of 2 Dose 
Regimens of Intravenous TAK-954 for the Prophylaxis and 
Treatment of Postoperative Gastrointestinal Dysfunction in Patients 
Undergoing Large- and Small-Bowel Resection 
TAK-954-2004
SAP Version and Date: 
Version 3.0: 18-May-2021 
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STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-954-2004
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Ranging Study to Evaluate the 
Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and 
Treatment of Postoperative Gastrointestinal Dysfunction in Patients Undergoing Large– and 
Small–Bowel Resection
PHASE 2b
Version: Final Version 3
Date: 07 May 2021
Prepared by:
, Ph.D
, Statistical & Quantitative Sciences, 
Takeda Development Center Americas, Inc.
   Based on:
Protocol Version: Amendment 05
Protocol Date: 23 March 2021
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
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Statistical Analysis Plan
07 May 2021
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Statistical Analysis Plan
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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
LIST OF ABBREVIATIONS......................................................................................................5
3.0
OBJECTIVES .................................................................................................................7
3.1
Primary Objective......................................................................................................7
3.2
Secondary Objectives.................................................................................................7
3.3
Exploratory Objectives ..............................................................................................7
3.4
Study Design .............................................................................................................7
4.0
ANALYSIS ENDPOINTS.............................................................................................11
4.1
Primary Endpoint.....................................................................................................11
4.2
Secondary Endpoints ...............................................................................................11
4.3
Safety and Tolerability Endpoints ............................................................................11
4.4
Exploratory Endpoints .............................................................................................12
5.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
6.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
6.1
General Principles....................................................................................................13
6.1.1
Definition of Study Day, Baseline and Study Visit Windows...........................13
6.1.2
Grouping of Centers ........................................................................................15
6.2
Analysis Sets ...........................................................................................................15
6.3
Disposition of Subjects ............................................................................................16
6.4
Demographic and Other Baseline Characteristics.....................................................17
6.5
Medical History and Concurrent Medical Conditions...............................................17
6.6
Medication History and Concomitant Medications...................................................18
6.7
Study Drug Exposure and Compliance.....................................................................18
6.8
Summary of the Impact due to COVID-19...............................................................19
6.9
Efficacy Analysis.....................................................................................................19
6.9.1
Analysis of Primary Efficacy Endpoint ............................................................20
6.9.2
Analysis of Secondary Efficacy Endpoints.......................................................22
6.9.3
Analysis of Exploratory Efficacy Endpoints.....................................................22
6.9.4
Analysis of Patient Reported Outcomes ...........................................................23
6.9.5
Missing Items on Rating Scales .......................................................................24
6.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................24
6.10.1
Pharmacokinetic Analysis................................................................................24
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6.10.2
Pharmacodynamic Analysis.............................................................................24
6.11
Other Outcomes.......................................................................................................24
6.12
Safety Analysis........................................................................................................25
6.12.1
Adverse Events................................................................................................25
6.12.2
Clinical Laboratory Evaluations.......................................................................26
6.12.3
Vital Signs and Weight ....................................................................................27
6.12.4
12-Lead ECGs.................................................................................................27
6.12.5
Other Observations Related to Safety...............................................................28
6.13
Interim Analysis ......................................................................................................28
6.14
Changes in the Statistical Analysis Plan...................................................................29
7.0
REFERENCES..............................................................................................................35
LIST OF IN-TEXT TABLES
Table 6.a
Visit Windows ...................................................................................................14
Table 6.b
Primary, Secondary and Exploratory Variables ..................................................20
LIST OF IN-TEXT FIGURES
Figure 3.a
Schematic of Study Design Prior to Protocol Amendment 5.................................9
Figure 3.b
Schematic of Study Design by Protocol Amendment 05.....................................10
LIST OF APPENDICES
Appendix A
The 12-Item Short Form Health Survey (SF-12).................................................36
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................37
Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs..............................38
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........39
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LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CEC
cardiovascular endpoint committee
CI
Confidence interval
CNS
central nervous system
CRP
C-reactive protein
CV
cardiovascular
CYP
cytochrome P-450
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
case report form (electronic or paper)
EQ-5D
Euro Quality of Life-5 dimensional questionnaire
ERP
enhanced recovery pathway(s)
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GIP
glucose-dependent insulinotropic peptide
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
IA
interim analysis
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IL
interleukin
IMC
internal monitoring committee
IND
Investigational Drug Application
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
LFT
liver function tests
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LOCF
Last observation carried forward
LOS
length of stay
LS
Least squares
MCP
monocyte chemoattractant protein
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NG
nasogastric
NRS
numerical rating scale
PD
pharmacodynamic
PK
pharmacokinetic
POGD
postoperative GI dysfunction
PONV
postoperative nausea and vomiting
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SF-12
12-Item Short Form Health Survey
SUSAR
suspected unexpected serious adverse reaction
SVT
supraventricular tachycardia
VT
ventricular tachycardia
Takeda
Takeda Development Center Americas, Inc
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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3.0
OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to assess the efficacy and safety of IV TAK-954 for 
accelerating the recovery of GI function postsurgery in patients undergoing open or 
laparoscopic-assisted partial small- or large-bowel resection.
3.2
Secondary Objectives
The secondary objectives of this study are:

To determine efficacy and safety of preoperative dosing of IV TAK-954 relative to
preoperative and postoperative regimens of up to 10 days of IV TAK-954 for accelerating the
recovery of GI function postsurgery.

To determine the relative efficacy and safety of 0.1 and 0.5 mg IV TAK-954 given either
preoperatively alone or preoperatively and postoperatively compared to placebo of up to 10
days or resolution of GI dysfunction postsurgery for accelerating the recovery of GI function
postsurgery.

To determine the PK of TAK-954 in patients undergoing major abdominal surgery.
3.3
Exploratory Objectives
The exploratory objectives are:

To assess the effect of IV TAK-954 on circulating markers of inflammation, including but
not limited to IL-6, IL-10, MCP-1 and CRP postsurgery.

To assess the effect of IV TAK-954 on circulating markers associated with GI motility and/or
nausea.

To gain preliminary estimates of the incidence rate of postoperative complications and
prolonged POGD (≥5 days) based on the type of surgery (laparoscopic vs open surgery), use
of opioids, duration of surgical procedure, and ASA scores.

To gain preliminary estimate of the effect of TAK-954 in preventing recurrence of GI
dysfunction postsurgery.

To gain preliminary estimate of the effect of TAK-954 in preventing POGD complications.
3.4
Study Design
This phase 2, randomized, placebo-controlled, parallel 5-group, double-blind study is designed to 
determine: (1) if TAK-954 decreases the duration of GI dysfunction in patients undergoing major 
abdominal open or laparoscopic-assisted surgeries that involve significant bowel manipulation, 
(2) whether preoperative dosing alone or a preoperative and postoperative dosing regimen is the
most effective dosing regimen to decrease the duration of POGD and improve clinical outcomes,
and (3) the most appropriate dose and dosing regimen to advance into phase 3.
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Subjects will be randomized in a 1:1:1:1:1 ratio into 1 of 5 parallel treatment groups:

Regimen 1: Placebo (NS 100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function (ie, resolution of POGD) or for up 
to 10 days.

Regimen 2: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 3: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 4: TAK-954 (0.1 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to 10 
days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to 10 
days.
Subject randomization will be stratified by laparoscopic and open surgery procedures.
With this Protocol Amendment 05, the planned total sample size is approximately 180 subjects. 
Two of the above TAK-954 regimens are discontinued based on internal monitoring committee 
(IMC) recommendations. As a result, eligible subjects will be equally randomized to into 1 of 3 
of the remaining parallel treatment groups:

Regimen 1: Placebo (NS 100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function (ie, resolution of POGD) or for up 
to 10 days

Regimen 3: : TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
postoperation until return of upper and lower GI function or for up to 10 days.

Regimen 5: TAK-954 (0.5 mg/100 mL infusion over 60 minutes) preoperation and daily 
placebo infusions postoperation until return of upper and lower GI function or for up to 
10 days.
It is standard of practice for the postoperative care of patients after colorectal surgery to 
implement an ERP to reduce the time to recovery of GI function (motility). To provide a 
consistent ERP as baseline therapy for all subjects, they will receive the same core features of an 
ERP for postoperative care as outlined below:
Core ERP:

Minimize opioid use while maintaining adequate pain control through use of multimodal 
analgesia. Suggested analgesics include opioid alternatives, such as nonsteroidal anti-
inflammatory drugs (eg, ketorolac tromethamine IV), acetaminophen (paracetamol), or oral 
pregabalin, when possible. It is recommended that at least 2 different analgesics with 
different mechanism of action are tried and failed before prescribing opioids.
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
Maintenance of euvolemia and normal salt and electrolyte state in perioperative period.

No routine use of prophylactic NG tubes postsurgery. NG tubes should only be used if there 
is a documented medical reason to justify them.

Use of a standardized risk-based strategy for PONV prophylaxis: use of preoperative 
antiemetic prophylaxis in patients with 1 or more risk factors of the simplified Apfel Score 
(female gender, planned postoperative use of opioids, nonsmokers, history of PONV/motion 
sickness).

Early oral feeding postsurgery when possible. Clear liquids after the surgery on Day 1, 
advancing to soft diet on Day 2 if tolerant to liquids (no nausea or vomiting).

Early mobilization starting after the surgery on Day 1 when possible.
The Schematics of the study design prior to Protocol Amendment 05 are included in Figure 3.a. 
and with the discontinuation of 2 treatment regimens and removal of the second IA in Figure 3.b
A schedule of assessments is listed in the protocol Appendix A.
Figure 3.a
Schematic of Study Design Prior to Protocol Amendment 5
Abbreviations: IA, interim analysis; PBO, placebo.
PBO
T1*
T2*
T3*
25
25
25
25
IA #1 
Decisions based 
on efficacy and 
safety of each arm 
(potential study 
modification 
including futility, 
dose adjustment, 
dose/dosing 
regimen decisions, 
and sample size 
adjustments).
Validation of 
power calcula ion
Doses/regimens may be modified.
PBO
TO1**
TO2**
+ 25, Total: 50
+ 25, Total: 50
+ 25, Total: 50
25 subjects/arm
Total: 125 subjects
Add 25 subjects/arm
Total: up to 225 subjects
IA #2
Decisions based 
on efficacy and 
safety of each arm 
(Goal is to identify 
the most 
promising/safe 
dose/regimen).
Valida ion IA #1
PBO
+50, Total: 100
Add 50 subjects/arm
Total: up to 375 subjects
TOX***
+50, Total: 100
TOY****
+50, Total: 100
(Possible)
T1 = TAK-954 0.1 mg/100 mL infusion preoperative and daily
T2 = TAK-954 0.5 mg/100 mL infusion preoperative and daily
T3 = TAK-954 0.1 mg/100 mL infusion preoperative only 
T4 = TAK-954 0.5 mg/100 mL infusion preoperative only 
Doses/regimens may be modified.
**TO1 & TO2 & TO3 = Optimal 
dose carried over after IA #1
***TOX = Optimal dose continues after IA #2.
****TOY = Could continue if deemed 
valuable as alternative dose.
T4*
25
TO3**
+ 25, Total: 50
(Possible)
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Figure 3.b
Schematic of Study Design by Protocol Amendment 05
Abbreviations: IA, interim analysis; PBO, placebo.
Criteria for resolution of upper and lower GI function is time to tolerance of solid food (defined 
as no vomiting or no clinically significant nausea for 1 calendar day after the first solid meal) 
and time to first spontaneous bowel movement (whichever occurs later), up to Day 10 
postsurgery.
Following hospital discharge, subjects will be instructed to contact their physician if they have 
recurring symptoms suggestive of POGD to evaluate the need for hospital readmission in case of 
relapse. All subjects will return to the clinic 14 days post last dose (±4 days) for follow-up visits. 
Subjects will be contacted by phone 30 (±3 days) and 90 (±7 days) days posttreatment for a 
safety follow-up.
Two preplanned interim analyses (IAs) will be conducted when a priori enrollment goals have 
been achieved. Bayesian approach will be applied after these IAs for decision making for 
potential study modification including futility, dose and dosing regimen decision, and sample 
size adjustment. By the protocol amendment 05, the second IA is removed from the protocol.
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4.0
ANALYSIS ENDPOINTS
4.1
Primary Endpoint 
The primary efficacy endpoint is time from the end of surgery to resolution of upper and lower 
GI function (eg, time to tolerance of solid food [defined as first occurrence of no vomiting or no 
clinically significant nausea for 1 calendar day after a solid meal] and time to first spontaneous 
bowel movement, whichever occurs later) up to Day 10 postsurgery. 
4.2
Secondary Endpoints
The secondary endpoints for this study will be:

Time from the end of the surgery (time the incision is closed) until ready for discharge 
(defined as the time until the subject presents effective intestinal transit [spontaneous bowel 
movement], tolerates solids without vomiting or clinically significant nausea for 1 calendar 
day after a solid meal, has satisfactory pain control with oral analgesics, and is medically 
stable/free of complications).

Time from the end of surgery until the discharge order is written.

Time from the end of the surgery to discharge from hospital.

Time from end of surgery to tolerance of solid food (defined as first occurrence of intake of 
solids without vomiting or clinically significant nausea for 1 calendar day after a solid meal), 
up to Day 10 postsurgery.

Time from end of surgery to first spontaneous bowel movement (defined as a stool not 
induced by the use of enemas or laxatives) up to Day 10 postsurgery.

Percent of subjects with POGD ≥5 days defined as subjects unable to tolerate solid foods, 
take anything by mouth, or requiring insertion or reinsertion of NG at or after 5 days 
postsurgery.

Percentage of subjects requiring insertion of NG tube postsurgery, for drainage and symptom 
relief in case of persistent nausea and vomiting postsurgery up to Day 24 postsurgery (up to 
10-day treatment period plus 14-day observation period post last dose for recurrence of 
symptoms).

Time from end of surgery to first flatus up to Day 10 postsurgery. 

Observed plasma concentration of TAK-954 at the end of infusion on Day 1. 
4.3
Safety and Tolerability Endpoints
Safety and tolerability will be evaluated based on the occurrence of AEs, physical examination 
findings, vital signs and weight, electrocardiograms, and clinical laboratory parameters 
(chemistry, hematology).
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4.4
Exploratory Endpoints
The exploratory endpoints for this study will be:

Change in circulating inflammatory markers including but not limited to IL-6, IL-10, MCP-1, 
and CRP, preoperatively compared with postoperatively across different treatment groups.

Change in GIP and cortisol preoperatively compared with postoperatively across different 
treatment groups.

Incidence rate of POGD recurrence for 14 days post last dose.

Percentage of subjects with unplanned hospital readmissions due to recurrence of POGD.

Percentage of subjects with postoperative complications, such as pneumonia, acute kidney 
failure, or documented anastomotic leak.

Percentage of subjects requiring reoperation due to postoperative complications.

Health-related quality of life as measured by 12-Item Short Form Health Survey (SF-12) and 
EuroQol 5-Dimensions Questionnaire (EQ-5D).

Percentage of subjects with postoperative nausea and vomiting (PONV) within 24 hours after 
surgery, from Day 2 until discharge and at follow-up; defined as patients presenting with 
emetic events (nausea, vomiting, or retching) or requiring use of antiemetics.

Peak nausea severity score from Day 1 until discharge using a numerical rating scale.

Time from the end of the surgery to the first insertion of NG tube (for those requiring 
insertion of NG tube postsurgery). 

Percentage of subjects presenting complications or prolonged POGD (≥5 days) based on 
opioid use, type of surgery, duration of the surgical procedure, and ASA scores. 
5.0
DETERMINATION OF SAMPLE SIZE
Assuming 80% of subjects will have resolution of POGD at the end of study in the placebo 
group and 92.5% of subjects will have resolution of POGD at the end of study in the active 
TAK-954 doses, a total of approximately 300 subjects (100 per treatment group) will provide 
80% power with a 0.05 2-sided significance level under Protocol Amendment 04.
In order to mitigate the statistical, clinical, and operational risks to this study in light of the 
COVID-19 pandemic, the probability of success of the study is re-estimated by blinded 
assessments using efficacy assumptions of Protocol Amendment 04. Specifically, by the removal 
of the second IA per this amendment and changing the statistical significance level from 2-sided 
5% to 1-sided 5%, the resulting sample size is an overall total of 50 subjects for each remaining 
arm (Figure 3.b). Under these revised assumptions and the dropping of 2 arms, an overall total of 
approximately 180 subjects for the study will provide approximately 80% probability, for at least 
1 remaining TAK-954 treatment arm, that TAK-954 is superior to placebo in time to resolution 
of upper and lower GI function at 1-sided 5% significance level for the final analysis.
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6.0
METHODS OF ANALYSIS AND PRESENTATION
6.1
General Principles 
All tabulations of analysis results will include summaries for the following treatment groups: 

Placebo — Placebo preoperation and daily postoperation

TAK-954 0.1mg DAILY — TAK-954 0.1mg preoperation and daily postoperation

TAK-954 0.5mg DAILY — TAK-954 0.5mg preoperation and daily postoperation

TAK-954 0.1mg PRE — TAK-954 0.1mg preoperation and daily placebo

TAK-954 0.5mg PRE — TAK-954 0.5mg preoperation and daily placebo
Categorical data will be summarized as the number and percentage of subjects in each category. 
Percentages will be reported to 1 decimal place. 
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. 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. 
All statistical tests will be 1-tailed at α=0.05 level for significance and 90% confidence intervals 
(CIs) will be reported for estimate of interest unless otherwise stated. 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.
Study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings where indicated. The actual day relative to the first dose will be presented, where 
applicable.
All statistical analyses will be performed using the SAS System Version 9.4 or higher.
6.1.1
Definition of Study Day, Baseline and Study Visit Windows
A windowing convention will be used to determine the analysis value for a given study visit that 
applies to observed data.
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF). Other study days are defined relative to Study Day 1. Study days prior 
to the first dose of study drug will be calculated as: [date of interest – date of first dose of study 
drug]. Study days on or after the first dose of study drug will be calculated as: [date of interest –
date of first dose of study drug + 1]. 
For each study visit, a window will be defined such that the lower and upper bounds of each 
window is generally the midpoint between 2 consecutive study visits. The visit windows and 
applicable study day ranges are presented below in Table 6.a.
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More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used.
In the safety data summary, the treatment period ‘End of Treatment’ values will be defined 
irrespective of falling in a particular window. Hence, the windowed Day 10 value may be 
different than the End of Treatment visit value.
Table 6.a
Visit Windows
Nominal Visit Day
ECG
Labs
Vital Signs
ERP
EQ-5D, SF-12
Baseline (a)
≤1
≤1
≤1
≤1
≤1
1
1(b)
1(c)
2
2(b)
≥2
2
≥2
3
3
4
3—4
4
5
5
6
5—6
6
7
7
8
7—8
8
9
9
10
≥9
10—12
2—12
16-24 Interim Follow-up 
(14 days post last dose)
≥13
≥13
(a) Some baseline evaluations are performed on Study Day 1 before study drug administration. While some other 
baseline evaluations are performed on Study Day -1. 
(b) ECG will be collected prior to and at the end of the infusion on Day 1; approximately 1, 2, and 8 hours after the 
start of the 60-minute infusion on Day 2; and at the end of the infusion on every other day of treatment (Days 4, 6, 8, 
and 10). 
(c) Vital signs will be collected before and after surgery on Day 1, at least every 12 hours on Days 2 to 10.
In general, the baseline value for a variable is defined as the last non-missing observation prior to 
the first dose of double-blind study medication (visit date/time ≤ first dose date/time), including 
the screening value, if necessary. 
Adverse events that start more than 30 days after the last dose of double-blind study medication 
(start date – last dose date >30) will be listed, but excluded from the summaries and analyses. 
For other safety data, data that are obtained more than 14 days after the last dose of double-blind 
study medication (visit date – last dose date >14) will be listed, but excluded from summaries 
and analyses.
For GI dysfunction and resolution related endpoints, specific rules for summary and analyses 
will be defined in Section 7.8. 
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The study window convention will not be applied to the data listings. The data listings will 
display the raw data as collected.
6.1.2
Grouping of Centers
In some statistical analysis, center effect will be investigated as a covariate in the statistical 
models. Before unblinding the data, centers that are considered small (<10 subjects) will be 
pooled with geographically similar centers to minimize artifacts in the statistical analyses from 
imbalances in subject counts within the centers.
Center(s) with less than 10 subjects enrolled will be pooled with the nearest center that enrolled 
more than 10 subjects. The pooling will start first within each country; if it is still small, other 
countries within the same geographical region (for example, Western Europe, Eastern Europe, 
and USA) will also be considered. The pooled centers within a region that still have less than 10 
subjects will be kept as they are and will not be pooled with centers in other regions.
The pooling of the centers will be reviewed and approved by the clinical and statistical team for 
agreement prior to unblinding, and is then used in the appropriate analyses once the database is 
locked and unblinded.
6.2
Analysis Sets
Safety Set: The safety set will include all subjects who were randomized and received at least 1 
dose of double-blind study medication. In safety summaries, subjects will be analyzed according 
to the treatment they received. If a subject receives more than 1 treatment, the actual treatment 
will be defined as the one that is used most frequently. If the 2 most common treatments are used 
with equal frequency, then the actual treatment will be defined as the one with highest dose level.
Full Analysis Set (FAS): The FAS will include all subjects who were randomized, received at 
least 1 dose of study drug, and have at least 1 valid postbaseline on-treatment primary efficacy 
evaluation (bowel movement or tolerating solid food). In efficacy summaries and analyses, 
subjects will be analyzed by the treatment to which they were randomized.
Per-Protocol Set (PPS): The PPS will include all FAS subjects who had no important protocol 
violations that could confound the interpretation of the primary analyses based on the FAS. The 
categories of these important protocol violations leading to subject’s exclusion from FAS to form 
PPS include: 
–
No evaluable post-baseline on-treatment primary efficacy evaluation.
–
Receiving incorrect study medication that leads to a treatment change.
–
Low study drug compliance (<80%) or missed study drug for at least 3 consecutive days 
prior to resolution of upper and lower GI function.
–
Violate ANY core features of ERP listed below.

Minimize opioid use while maintaining adequate pain control through use of 
multimodal analgesia. Suggested analgesics include opioid alternatives such as 
nonsteroidal anti-inflammatory drugs (eg, ketorolac tromethamine IV), 
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acetaminophen (paracetamol), or oral pregabalin when possible. It is recommended 
that at least 2 different analgesics with different mechanism of action are tried and 
failed before prescribing opioids.

Maintenance of euvolemia and normal salt and electrolyte state in perioperative 
period.

No routine use of prophylactic nasogastric (NG) tubes postsurgery. NG tubes should 
only be used if there is a documented medical reason to justify them.

Use of a standardized risk-based strategy for postoperative nausea and vomiting 
(PONV) prophylaxis: use of preoperative antiemetic prophylaxis in patients with 1 or 
more risk factors of the simplified Apfel Score (female gender, planned postoperative 
use of opioids, nonsmokers, history of PONV/motion sickness).

Early oral feeding postsurgery when possible. Clear liquids after the surgery on Day 
1, advancing to soft diet on Day 2 if tolerant to liquids (no nausea or vomiting).

Early mobilization starting after the surgery on Day 1 when possible.
Other important protocol violations leading to subject’s exclusion from FAS will be identified 
during blinded data reviews and finalized prior to unblinding of subject’s treatment assignment 
and database lock. 
PK Analysis Set: The PK analysis set consists of all subjects who were randomized, received at 
least 1 dose of TAK-954 and have at least 1 measurable postdose plasma for TAK-954.
6.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version, will be tabulated.
Disposition of all screened subjects will be summarized descriptively, including a summary of 
the number of screened subjects, the number of subjects eligible/not eligible for randomization, 
and the primary reason for ineligibility for randomization. The number of screen failures and 
primary reason of screen failures will also be summarized.
Disposition for all randomized subjects will be summarized by treatment group and overall. 
Disposition categories include:

Number and percentage of subjects randomized but not dosed, 

Number and percentage of subjects completed study drug, 

Number and percentage of subjects prematurely discontinued study drug along with the 
primary reason for study drug discontinuation, and 

Number and percentage of subjects completed all study visits
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
Number and percentage of subjects discontinued from the study along with the primary 
reason for discontinuation of study visits.
The number and percentage of randomized subjects by country and site will be summarized 
based on the Randomized Set. Important protocol deviations will be summarized based on the 
Randomized Set. Reasons for exclusion from the FAS to form PPS will be summarized based on 
the FAS. 
The analysis sets defined in Section 7.2 will also be summarized.
All individual disposition data will be listed by treatment, study center and subject number.
6.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics including sex, age, age category (18-64 years, 65-84 
years, 85 years and over), ethnicity, race, height, weight, BMI, substance abuse, surgery bowel 
(small and large), and subject surgery procedures (Laparoscopic and open) will be listed and 
summarized for each treatment group and overall. The demographic and baseline characteristics 
summary will be based on all randomized subjects.
Baseline values for the quality of life parameters (EQ-5D and SF-12) will also be presented for 
each treatment group and overall based on all randomized subjects.
Compliance with overall and individual core ERP recommendations will be summarized based 
on randomized subjects. 
All individual demographic and baseline data will be listed by treatment, study center and 
subject number.
6.5
Medical History and Concurrent Medical Conditions
Medical history refers to significant conditions/diseases that stopped at or prior to Screening 
(time of informed consent). Concurrent medical conditions are those significant ongoing 
conditions/diseases or present at Screening (time of informed consent). 
Medical history and concurrent medical conditions will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) latest version and will be summarized by treatment group and 
overall using System Organ Class (SOC) and MedDRA preferred term. The table will include 
number and percentages of subjects, and will be sorted in alphabetical order by SOC. Within an 
SOC, preferred terms 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 
or symptoms. Summaries will be based on all randomized subjects.
All medical history and concurrent medical condition data will be listed by treatment, study 
center and subject number.
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6.6
Medication History and Concomitant Medications
The medication history and concomitant medications are defined as follows:

Medication history refers to the medication that the study subjects stopped taking at or within 
90 days prior to the Screening (time of informed consent).

Concomitant medication is defined as medication that the study subjects continued taking or 
took from Screening (time of informed consent) through end of study:

Concomitant medication that started and stopped prior to baseline (ie, stop date ≥ first 
screening visit date, and stop date < first dose date).

Concomitant medication that started prior to and was ongoing at baseline (ie, start date 
< first dose date, and stop date ≥ first dose date).

Concomitant medication that started after baseline but before or at last dose (ie, start date 
≥first dose date, and start date ≤ last dose date).

Concomitant medication taken during the study (ie, start date ≤ last dose date, and stop 
date ≥ first dose date.
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
Medication history and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary and summarized by giving the number and percentage of 
subjects by preferred term within each therapeutic class, with therapeutic class sorted in 
alphabetical order and preferred term sorted in decreasing frequency based on the total number 
of subjects. The number of subjects with medications in each selected therapeutic class will also 
be presented. If a subject takes 2 drugs belonging to the same class, he/she will only be counted 
once within that class. Summaries of medication history and concomitant medication, including 
COVID-19 vaccination and medications, will be based on all randomized subjects.
Number and percentage of subjects who took opioid analgesics will also be documented.
In addition, number and percentage of subjects who took antiemetic prophylaxis for PONV will 
be summarized, including also information on the number of Apfel risk factors to justify this 
indication and the specific antiemetic prescribed. 
All prior and concomitant medications will be listed by treatment, study center and subject 
number. 
6.7
Study Drug Exposure and Compliance
The summary of study drug exposure and compliance will be based on the safety set.
Duration of exposure to double-blind study medication is defined as (date of last dose – date of 
first dose +1). Treatment duration will be summarized by duration category in days (1 to 4 days, 
≥ 5 days) and the number of subjects in each duration category by treatment group. Treatment 
duration (days) will also be summarized as a continuous variable using descriptive statistics.
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Percent of study drug compliance is defined as number of infusions administrated / (date of last 
dose – date of first dose +1)×100%. 
For each treatment group, study medication compliance will be summarized by compliance 
category (<80% and ≥80%) and the number of subjects in each compliance category. Study 
medication compliance will also be summarized as a continuous variable using descriptive 
statistics for each treatment group.
All study drug administration and accountability data will be listed by treatment, study center, 
and subject number. The following variables will be listed: subject identifier, first and last dose 
dates, medication identification number, infusion date, and percent compliance. 
6.8
Summary of the Impact due to COVID-19 
All study data about the impact on study participants due to COVID-19 will be provided in by-
subject listings for all randomized subjects.
6.9
Efficacy Analysis
The analyses and summaries for efficacy will be based on the FAS. 
In the final analyses of efficacy endpoints, for the two discontinued TAK-954 arms, only the 
summary statistics (n, mean, SD, median, minimum, and maximum for continuous endpoints; 
number and percentage of subjects for categorical data; the number and percentages of events 
and censoring, median, minimum, and maximum for time to event endpoint) will be provided; 
for the remaining treatment groups after IA, the inferential statistics (point estimates of interest 
and 90% confidence intervals (CIs) and 1-sided p-values) for each treatment group and the TAK-
954 doses/regimens in comparison with placebo will be provide along with summary statistics.
If more than 5% of the total subjects in the FAS have important protocol violations leading to 
subject’s exclusion from FAS to form PPS, analyses based on the PPS will be performed for the 
primary efficacy endpoint and select secondary efficacy endpoints (i.e., Time from the end of the 
surgery until ready for discharge, Time from the end of surgery until the discharge order is 
written, Time from the end of the surgery to discharge from hospital, Time from end of surgery 
to tolerance of solid food up to Day 10 postsurgery, Time from end of surgery to first 
spontaneous bowel movement up to Day 10 postsurgery, and Time from end of surgery to first 
flatus up to Day 10 postsurgery). Otherwise, the analysis based on the PPS will be performed for 
the primary efficacy endpoint only.
If the inferential analyses of efficacy endpoints encounter either convergence issue or result in 
unstable estimation, the descriptive analysis method will be applied. 
The primary, secondary, and exploratory variables for this study are presented in Table 6.b.
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Table 6.b
Primary, Secondary and Exploratory Variables
Parameter
Description
Variable 
Type (a)
TIME_RESO
Time from end of surgery to resolution of upper and lower GI function 
1
TIME_FOOD
Time from end of surgery to tolerance of solid food 
1
TIME_BOWL
Time from end of surgery to first spontaneous bowel movement
1
TIME_DIS_RD
Time from end of surgery until ready for discharge
1
TIME_DIS_OW
Time from end of surgery until discharge order is written
1
TIME_DIS_HP
Time from end of surgery to discharge from hospital
1
TIME_FLA
Time from end of surgery to first flatus
1
TIME_NGT
Time from end of surgery to the insertion of NG tube
1
POGD_5
Percent of subjects with POGD >5 days
3
NGT_INS
Percentage of subjects requiring insertion of NG tube postsurgery
3
POGD_RECU
Incidence rate of POGD recurrence for 14 days post last dose 
3
HP_READ
Percentage of subjects with unplanned hospital readmissions due to recurrence 
of POGD 
3
PO_COMP
Percentage of subjects with postoperative complications
3
PO_COMP_RO
Percentage of subjects requiring reoperation due to postoperative complications
3
PO_COMP_PRL
Percentage of subjects presenting complications or prolonged POGD (≥5 days) 
based onopioid use, type of surgery, duration of the surgical procedure, and 
ASA scores
3
PO_PONV
Percentage of subjects presenting with postoperative nausea and vomiting 
(PONV) within 24 hours after surgery, from Day 2 until discharge, and at 
follow-up
3
NRS_PEAK
Peak nausea severity score at Day 1, until discharge, and at follow-up by NRS 
1
SF12_i
SF-36 sub-scale score i={physical functioning, role-physical, bodily pain, 
general health, vitality, social functioning, role emotional, mental health}
1
EQ5D_TOT
EQ-5D index, sum of the 5 item scores for the EQ-5D-5L descriptive system
1
EQ5D_VAS
Score of EQ visual analogue scale, ranged from 0 to 100
1
(a) 1 = continuous; 2 = categorical; 3 = binary.
6.9.1
Analysis of Primary Efficacy Endpoint
The primary endpoint is the time from the end of surgery to resolution of upper and lower GI 
function (eg, time to tolerance of solid food [defined as first occurrence of no vomiting or no 
clinically significant nausea for 1 calendar day after a solid meal] and first spontaneous bowel 
movement, whichever occurs later) up to Day 10 postsurgery.
With respect to the primary endpoint, the null hypothesis to be tested is that there is no difference 
between TAK-954 dose level and placebo in the time to resolution of upper and lower GI 
function. 
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The primary endpoint will be analyzed using the Cox proportional hazard model with treatment 
group as a single covariate, with Efron's method of tie handling, stratified by randomization 
stratification factor. One-sided p-values for the pairwise comparisons between the remaining 
TAK-954 dose levels and the placebo will be calculated using Wald chi-square test from the Cox 
proportional hazards model. Hazard ratios of remaining TAK-954 dose levels to placebo and 
their 90% CIs will also be calculated from the Cox proportional hazards model. 
The Wald chi-square test statistic formula is as follow:
Where:

is the maximum likelihood estimator (MLE) 

is the expected Fisher information (evaluated at the MLE)
Median time to resolution of upper and lower GI function, which will also be used to express the 
magnitude of treatment effects in addition to hazard ratios, will be estimated by Kaplan-Meier 
survival analysis, and the difference (with 90% confidence intervals) between the TAK-954 dose 
levels and placebo will be provided. If an event does not occur for a patient during the study 
treatment period (maximum 10 days postoperatively), the patient will be assigned a censored 
time of 10 days postsurgery. 
The overall type I error rate is set at 5% (one-sided), i.e., the trial is considered to have reached 
the primary efficacy objective if the two corresponding p-values (one-sided) based on the Cox 
proportional hazards model for testing the null hypothesis (TAK-954 0.5mg DAILY vs Placebo 
and TAK-954 0.5mg PRE vs Placebo) are less than 5% (one-sided) OR either one is less than 
2.5% (one-sided).
For the primary endpoint, subgroup analyses by:

Surgery procedures (Laparoscopic, open),

Age (≤65, >65),

Sex (female, male),

Surgery Bowel (Small, large) 
and other variables, if necessary, will be performed if each of the subgroups contains at least 
20% of the total subjects in the study. The treatment groups will be compared within each 
subgroup. Additional exploratory analyses examining subgroup effect and treatment by subgroup 
interaction may be performed, if warranted.
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6.9.2
Analysis of Secondary Efficacy Endpoints
The secondary endpoints time from end of surgery to tolerance of solid food, time from end of 
surgery to first spontaneous bowel movement, time from end of surgery until ready for 
discharge, time from end of surgery until discharge order is written, time from end of surgery to 
discharge from hospital, and time to first flatus will be analyzed similarly to the primary 
endpoint. 
The percent of subjects with POGD >5 days and the percent of subjects requiring insertion of 
NG tube postsurgery will be analyzed using the Miettinen and Nurminen’s method stratified by 
randomization stratification factor for risk difference.
The following rules will be applied for the summary and analyses of the secondary endpoints: 

For the analysis of time to tolerance of solid food and time to first spontaneous bowel 
movement, if a resolution does not occur for a patient during the study treatment period 
(maximum 10 days postoperatively), the patient will be assigned a censored time of 10 days 
postsurgery.

For the analysis of time from end of surgery until ready for discharge, time from end of 
surgery until discharge orders are written, time from end of surgery to discharge from 
hospital, and time from end of surgery to first flatus, if an event does not occur for a patient 
during the study period, the patient will be assigned a censored time of 14 days post last 
dose.

For the summary and analysis of percent of subjects requiring insertion of NG tube 
postsurgery, insertion of NG tube postsurgery until two weeks of follow-up (Insertion date ≤ 
last dose date + 14) will be counted. 
6.9.3
Analysis of Exploratory Efficacy Endpoints
The time from the end of surgery to the insertion of NG tube will be analyzed similarly to the 
primary endpoint.
The incidence rate of POGD recurrence for 14 days post last dose, the percentages of subjects 
with unplanned hospital readmissions due to recurrence of POGD, the percent of subjects with 
postoperative complications, the percent of subjects presenting complications or prolonged 
POGD (>5 days), percent of subjects requiring reoperation due to postoperative complications,
and the percentages of subjects with postoperative nausea and vomiting (PONV) within 24 hours 
after surgery (from Day 2 until discharge and at follow-up; defined as patients presenting with 
emetic events [nausea, vomiting, or retching] or requiring use of antiemetics that will be 
identified during blinded data review and finalized prior to unblinding of subject’s treatment 
assignment and database lock) will be compared between TAK-954 dose levels and placebo 
using the Miettinen and Nurminen’s method stratified by randomization stratification factor for 
risk difference.
For the percent of subjects presenting complications or prolonged POGD (>5 days), the 
treatment groups will also be compared to placebo within the following subgroups:
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
Opioid use: Yes or no

Type of surgery: open or laparoscopic

Duration of the surgerical procedure: <2 hours, or >= 2 hours

ASA Score: <=2 or >2
The change from baseline (Day 1) in NRS nausea severity score will be analyzed by study visit 
using analysis of covariance (ANCOVA), with treatment, stratum, and pooled center as fixed 
factors, baseline score as covariate.
The following rules will be applied for the summary and analyses of the exploratory endpoints: 

For the analysis of time from end of surgery to the insertion of NG tube, if an insertion of NG 
tube does not occur for a patient during the study period, the patient will be assigned a 
censored time of 14 days for the event.

For the summary and analysis of incidence rate of POGD recurrence for 14 days post last 
dose, the percentages of subjects with unplanned hospital readmissions due to recurrence of 
POGD, the percent of subjects with postoperative complications, the percent of subjects 
presenting complications or prolonged POGD (>5 days), percent of subjects requiring 
reoperation due to postoperative complications, and the percentages of subjects with 
postoperative nausea and vomiting (PONV) within 24 hours after surgery, events happen 
postsurgery until two weeks of follow-up (event date ≤ last dose date + 14) will be counted. 
6.9.4
Analysis of Patient Reported Outcomes
The EQ-5D total score is the sum of the 5 item scores for the EQ-5D-5L descriptive system. 
Each item has 5 level score of perceived problem: 1 indicates no problem in relative health 
dimension, while 5 indicates extreme problems in relative health dimension.
The EQ-5D VAS is the score of the visual analogue scale, ranged from 0 to 100: 100 means the 
best health you can imagine, while 0 means the worst health you can imagine.
A detailed description of the SF-12 sub-scores calculation is found in Appendix A. The SF-12 
self-rated questionnaire yields a health profile based on the following subscales:

Physical Functioning: limitations in physical activities because of health problems.

Role-Physical: limitations in usual role activities because of physical health problems.

Bodily Pain.

General Health: perception of general health.

Vitality: energy and fatigue.

Social Functioning: limitations in social activities because of physical or emotional problems.

Role-Emotional: limitations in usual role activities because of emotional problems.

Mental Health: general mental health (psychological distress and well-being.
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Descriptive statistics in terms of score and change from baseline in the quality of life parameters 
(EQ-5D and SF-12) will be presented by visit and treatment group for each of the total and sub-
scores.
The change from baseline in the quality of life parameters (EQ-5D and SF-12) total scores and 
sub-scores will also be analyzed by visits using analysis of covariance (ANCOVA), with 
treatment, stratum, and pooled center as fixed factors, baseline score as covariate.
6.9.5
Missing Items on Rating Scales
For some reasons, subjects may not complete the full task as requested, or subjects used irregular 
procedure and/or questionable effort. In such cases, the data may be considered missing, 
unreliable and/or invalid. 
The general rule when individual items are missing from a multiple-item assessment is as 
follows: 
‒
Total score will be calculated as (sum of non-missing item scores) x total number of 
items / (number of non-missing items). 
‒
If more than 20% of the items are missing, the total score will be set to missing. The 
resulting calculated scores will be used in all analyses.
6.10
Pharmacokinetic/Pharmacodynamic Analysis
6.10.1
Pharmacokinetic Analysis
No formal noncompartmental PK analyses will be performed on concentration-time data. The
observed plasma concentrations of TAK-954 will be summarized by dose/regimen at study
scheduled day/time point where appropriate. The individual concentration-time data for TAK-
954 and its metabolites will be included in listings. Details will be provided in the Clinical 
Pharmacology Analysis Plan (CPAP). 
6.10.2
Pharmacodynamic Analysis
Not applicable.
6.11
Other Outcomes
Change in circulating inflammatory markers including but not limited to IL-6, IL-10, MCP-1, 
CRP and change in GIP and cortisol preoperatively compared to postoperatively will be analyzed 
by study visits using analysis of covariance (ANCOVA), with treatment, stratum, and pooled 
center as fixed factors, baseline value as covariate. 
Considering that glucose-dependent insulinotropic peptide (GIP) is no longer collected under
protocol amendment 05, if the ANCOVA of GIP results in convergence issue due to limited 
samples, the ANCOVA of GIP will be simplified (e.g., removing the pooled center and etc. until 
convergence issue is resolved) to ensure robust statistical estimate.
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6.12
Safety Analysis
All safety summaries will be based on the safety set. Safety summaries will include descriptive 
statistics for values, changes, and incidence of events for all treatment groups combined in 
addition to summary by treatment.
6.12.1
Adverse Events
All adverse events will be coded using MedDRA latest version. In this dictionary, each verbatim 
term is coded to a lower level term, and then mapped to a preferred MedDRA term, which is then 
mapped to an SOC. All adverse events, including the COVID-19 related adverse events, will be 
included in the data listings but only treatment emergent adverse events will be included in the 
summary 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 (AE onset date – date of last dose ≤30). AEs with missing onset dates will be 
summarized with TEAEs regardless of severity and relationship to study medication.
The following summaries will be presented:

Overview of TEAEs during the study - number and percentage of subjects, number of events.

TEAEs by SOC and PT - number and percentage of subjects.

TEAEs by PT - number and percentage of subjects.

Severity of TEAEs by SOC and PT - number and percentage of subjects.

Relationship of TEAEs by SOC and PT - number and percentage of subjects.

Drug-related TEAEs by SOC and PT - number and percentage of subjects.

TEAEs Related to Study Procedure by SOC and PT - number and percentage of subjects.

TEAEs leading to study discontinuation by SOC and PT - number and percentage of 
subjects.

Serious treatment-emergent AEs by SOC and PT - number and percentage of subjects, 
number of events.

Treatment-emergent Adverse Events of Special Interest by SOC and PT - number and 
percentage of subjects, number of events.

Most Frequent (>=5%) Treatment-emergent Non-serious AEs by SOC and PT - number and 
percentage of subjects, number of events.

Suspected MACE up to 90 days after last dose - number and percentage of subjects.
SOCs will be sorted in alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with the preferred term among all the treatment 
groups.
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In the high-level adverse event summary tables, TEAEs will be summarized regardless of 
severity and relationship to study drug. Within each subject, multiple reports of events that map 
to a common MedDRA term will be counted only once.
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting 1 or more events that map to the 
given MedDRA term.
At the SOC level, the summary tables will present the number of subjects reporting 1 or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC.
In selected summaries (see above), adverse events will be summarized by the number of events 
reported in addition to the number and percentage of subjects with events.
For the summary of TEAEs by SOC, preferred term and maximum severity, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once by the maximum intensity of the episode (preferred term). Similarly, if a subject has 
more than 1 adverse event within an SOC, the subject will be counted only once by the 
maximum severity in that SOC.
TEAEs classified in the eCRF as possibly or probably related to the study medication will also 
be summarized by preferred term and SOC. If a subject experiences more than 1 episode of a 
particular coded adverse event, the subject will be counted only once by the most related report 
for the preferred term. Similarly, if a subject has more than 1 adverse event within an SOC, the 
subject will be counted only once by the most related report in that SOC. Adverse events with 
missing relationship will be classified as having the highest relationship to study drug.
All adverse events will be listed by treatment, study center, subject number and onset date of the 
adverse event. The listing will contain: subject identifier, age, sex, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity (mild, moderate or severe), action taken concerning study 
drug, causality to study drug, the outcome, whether the adverse event was an SAE and whether 
the event was an adverse event of special interest (AESI).
Special listings for TEAEs leading to study discontinuation, SAEs, deaths, and AE of special 
interest will also be presented.
6.12.2
Clinical Laboratory Evaluations
The local laboratory will perform laboratory tests for hematology and serum chemistries. The 
results of laboratory tests will be returned to the investigator, who is responsible for reviewing 
and filing these results. Any clinically significant laboratory result will be captured as an AE as 
per the CTCAE v5.0.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical safety 
laboratory variables will be summarized for baseline, postbaseline values, and change from
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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.
The number and percentage of subjects with abnormal values observed post-Baseline will be 
presented.
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.
Summaries and listings of laboratory data will be presented in Systeme International (SI) unit. 
Laboratory data outside of the normal reference range will be flagged on the listing along with 
values meeting MAV criteria
6.12.3
Vital Signs and Weight
Vital signs and weight at scheduled visits and their changes from Baseline will be summarized 
for each treatment group and overall using descriptive statistics by visit and end of treatment. 
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.
6.12.4
12-Lead ECGs
The ECG parameters include heart rate, PR interval, QRS duration, QT interval, and QT interval 
with Fredericia’s corrections (QTcF).
ECG variables at scheduled visits and their changes from Baseline will be summarized for each 
treatment group and overall using descriptive statistics by study visit and end of treatment. 
A shift table for the investigator’s ECG interpretation will provide the number of subjects in each 
of the appropriate categories (Normal, Abnormal but not clinically significant, or Abnormal and 
clinically significant) at the scheduled visit relative to the Baseline status. 
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 
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abnormal ECG measurement will be summarized. All post dose ECGs within 7 days of the last 
dose, including both scheduled and unscheduled measurements, will be included in the MAV 
summaries. The mapping of the subjects who meet the MAV criteria will be listed as a table.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
6.12.5
Other Observations Related to Safety
Not applicable.
6.13
Interim Analysis
Two preplanned interim analyses will be conducted when a priori enrollment goals have been 
achieved. Additional interim analyses may be added if deemed appropriate based on study 
findings from preplanned interim analyses. The first interim analysis will be conducted after 
approximately 125 subjects (25 per arm) have completed or withdrawn from the study. The 
second interim analysis will be conducted after approximately 50 subjects per arm have 
completed or withdrawn from study. The interim analyses will include the key safety and 
efficacy data available for subjects identified at the time of the interim analysis data cut. 
Following each interim analysis, Bayesian approach for decision making will be implemented 
for the potential study modification including futility, dose and regimen decision, and sample 
size adjustment. An internal monitoring 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 unblinded interim analysis results and make 
recommendations for changes to the study based on the prespecified decision criteria. 
At each interim analysis, the decision criteria based on Bayesian approach with a non-
informative prior and safety consideration are as follow:

For each TAK-954 dose and dose regimen, the posterior probability will be calculated based 
on an expectation of at least 5% increase over placebo in resolution of upper and lower GI 
function given the observed interim data:
–
GO: if the posterior probability ≥ 70%. At this case, the relative dose or dose regimen 
will continue to be studied. 
–
No-Go: if the posterior probability < 30%. At this case, the relative dose or dose regimen 
will be dropped.
–
Gray Zone: if the posterior probability is between 30% and 70%. At this case, 
information from other doses or dose regimens will be taken into consideration. A 
decision will be made based on overall evaluation. 

The study will be terminated if all doses and dose regimens reach a “No-Go” criterion based 
on the posterior probability.

Any dose or dose regimen with clinically significantly higher incidence of serious adverse
events compared to placebo will be terminated regardless of the efficacy assessment. 
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Statistical Analysis Plan
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CONFIDENTIAL

The assumptions for sample size justification will be reviewed based on the interim data: 
–
After the second interim analysis, sample size for remaining treatment groups may be 
adjusted to ensure at least 80% power to detect a 10% difference between TAK-954 and 
placebo at end of study, however the sample size for each treatment arm will be capped at 
150 subjects.
Due to lack of good prior distributions, a frequentist approach instead of Bayesian approach was 
implemented for interim analysis. The details about the interim analysis were documented in the 
TAK-954-2004 Internal Monitoring Committee Charter (Version 2.0, Amendment 1.0, dated on 
04Dec2020) that was approved prior to the data cut (09Dec2020) for interim analysis.
6.14
Changes in the Statistical Analysis Plan 
The changes in the statistical analysis plan for protocol amendment 05 are summarized in the 
table below.
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Section 4.2 
Secondary 
Objectives
Clarified the secondary objective 
related to relative efficacy and safety 
was for accelerating the recovery of 
gastrointestinal (GI) function 
postsurgery.
Specified time window of up to 10 
days for study drug dosing for the 
secondary objective of determining 
efficacy and safety of preoperative 
dosing of intravenous TAK-954 
relative to preoperative and 
postoperative regimens.
Changes were made 
to reflect the 
corresponding 
changes in Protocol 
Amendment 05.
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Statistical Analysis Plan
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CONFIDENTIAL
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
2
Section 4.4 Study 
Design
Randomizations into 2 treatment 
groups (TAK-954 0.1 mg/100 mL 
preoperative and daily and TAK-954 
0.1 mg/100 mL preoperative only) 
have been discontinued based on the 
IA results.
Removed the second IA. Revised the 
language to reflect these changes.
Changes were made 
to reflect the 
corresponding 
changes in Protocol 
Amendment 05.
3
Figure 4.b 
Schematic of 
Study Design by 
Protocol 
Amendment 05
Section 6.0 
Determination of 
Sample Size
Added new figure to indicate study 
design after Protocol Amendment 5.
Revised sample size of remaining 
arms based on blinded assessments 
that were conducted using efficacy 
assumptions of the original protocol 
before the interim analysis (IA).
Changes were made 
to reflect the 
corresponding 
changes in Protocol 
Amendment 05.
4
Section 5.1 
Primary Endpoint
Section 5.2 
Secondary 
Endpoints
Section 5.4 
Exploratory 
Endpoints
Refined the definition of the primary 
efficacy endpoint time to resolution of 
upper and lower GI function by 
specifying “from the end of surgery”, 
defined tolerance to solid food as 
“first occurrence” of absence of 
vomiting or clinically significant 
nausea for 1 calendar day after a solid 
meal, and clarified that the follow-up 
time for the primary endpoint is up to 
Day 10 postsurgery.
Changes were made 
to reflect the 
corresponding 
changes in Protocol 
Amendment 05.
5
Section 7.1
General Principle 
Analysis Sets
Section 7.9
Statistical tests will be 1-tailed at 
α=0.05 level for significance and 90% 
confidence intervals (CIs) will be 
reported for estimate of interest.
Removed ‘received protocol specified 
Changes were made 
to reflect the changes 
of significance level 
from two-sided α = 
0.05 to one-sided α = 
0.05 and removing 
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Statistical Analysis Plan
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CONFIDENTIAL
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
Efficacy Analysis
Section 7.10.1
Pharmacokinetic 
Analysis
surgery’ in safety set and Used 
conservative principle for safety 
evaluation to determine the actual 
treatment when most frequently used 
treatment with tied frequency.
Removed 'received protocol-specified 
surgeries' and 'a valid baseline' in the 
definition for FAS.
Clarified the definition for PPS; the 
term ‘major protocol violation’ was 
changed to ‘important protocol 
violation’.
Added PK analysis set and provided 
details for the summary analysis of 
observed plasma concentration of 
TAK-954.
‘received protocol 
specified surgery’ in 
Protocol Amendment 
05.
Changes were made 
to the definition of 
safety set to match the 
definition in protocol
and used conservative 
principle for safety 
evaluation to 
determine the actual 
treatment when most 
frequently used 
treatment with tied 
frequency.
Changes were made 
to the definition of 
FAS to match the 
definition in protocol.
Clarified the 
definition for PPS and 
the term ‘major 
protocol violation’ 
was changed to 
‘important protocol 
violation’.
Added PK analysis set 
and provided details 
for the summary 
analysis of observed 
plasma concentration 
of TAK-954.
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Statistical Analysis Plan
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CONFIDENTIAL
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
6
Section 7.3 
Disposition of 
Subjects
Clarified the display of disposition 
summary and listing.
Clarified the display 
of disposition 
summary and listing.
7
Section 7.4 
Demographic and 
Other Baseline 
Characteristics
Simplified the analysis of 
demographic and baseline 
characteristics by removing the 
ANOVA for continuous variable and 
CMH for categorical variables.
Simplified the 
analysis of 
Demographic and 
Other Baseline 
Characteristics.
8
Section 7.6
Medication 
History and 
Concomitant 
Medications
Section 7.8 
Summary of the 
Impact due to 
COVID-19
Section 7.12.1
Adverse Events
Included COVID-19 vaccination and 
medications as part of the analysis of 
medication history and concomitant 
medications.
Added the details that COVID-19 
impact data will be provided in by-
subject listings.
Included COVID-19 related adverse 
events as part of the analysis of 
adverse events.
Included COVID-19 
vaccination and 
medications as part of 
the analysis of 
medication history 
and concomitant 
medications.
Added the details that 
COVID-19 impact 
data will be provided 
in by-subject listings.
Included COVID-19 
related adverse events
as part of the analysis 
of adverse events.
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Statistical Analysis Plan
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CONFIDENTIAL
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
9
Section 7.9
Efficacy Analysis
Section 7.9.1
Analysis of 
Primary Efficacy 
Endpoint
Section 7.9.2
Analysis of 
Secondary 
Efficacy 
Endpoints
Section 7.9.3
Analysis of 
Exploratory 
Efficacy 
Endpoints
Added general principles for 
analyzing and reporting the efficacy 
analyses of the two dropped arms and 
three remaining arms in the final 
analyses.
Added the rules for performing 
sensitivity analysis of efficacy 
endpoints based on PPS.
Added default analyses of efficacy 
endpoints to deal with either 
convergence issue or unstable 
estimation.
Specified the Efron’s method for 
handling ties in Cox model.
Specified the principles for evaluating 
primary efficacy objective.
Used the stratified Miettinen and 
Nurminen’s method for the analysis 
binary endpoints and calculating risk 
difference.
Clarified the endpoint of percentages 
of subjects with postoperative nausea 
and vomiting (PONV) within 24 hours
after surgery.
Clarified the analysis 
and reporting 
strategies for two 
dropped arms and 
three remaining arms 
in the final efficacy 
analyses.
Added the rules for 
performing sensitivity 
analysis of efficacy 
endpoints based on 
PPS.
Specified method for 
handling ties.
Specified the 
principles for 
evaluating primary 
efficacy objective.
Changed the method 
for the analysis of 
binary endpoints and 
calculating risk 
difference to reflect 
the corresponding 
changes in Protocol 
Amendment 05.
Clarified the endpoint 
of percentages of 
subjects with 
postoperative nausea 
and vomiting (PONV) 
within 24 hours after 
surgery.
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Statistical Analysis Plan
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CONFIDENTIAL
Statistical Analysis Plan (SAP) Amendment 02
Summary of Changes Since the Last Version of the Approved SAP
Change 
Number
Sections 
Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
10
Section 7.13
Interim Analysis
Clarified the Interim Analysis that was 
conducted in accordance with the 
approved protocol amendment 04.
Clarified the Interim 
Analysis that was 
conducted in 
accordance with the 
approved protocol 
amendment 04.
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Statistical Analysis Plan
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CONFIDENTIAL
7.0
REFERENCES
1. Bruce G. Wolff, MD, et al. Alvimopan, a Novel, Peripherally Acting µ Opioid Antagonist. 
Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of 
Major Abdominal Surgery and Postoperative Ileus.
2. Irinel Popescu, et al. The Ghrelin Agonist TZP-101 for Management of Postoperative Ileus 
After Partial Colectomy: A Randomized, Dose-Ranging, Placebo-Controlled Clinical Trial.
3. Grant Bochicchio, et al. Ghrelin Agonist TZP-101/Ulimorelin Accelerates Gastrointestinal 
Recovery Independently of Opioid Use and Surgery Type: Covariate Analysis of Phase 2 
Data.
4. Justin T Brady, et al. The use of alvimopan for postoperative ileus in small and large bowel 
resections.
5. Conor P. Delaney, et al. Postoperative upper and lower gastrointestinal recovery and 
gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo 
data from 3 randomized controlled trials.
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Statistical Analysis Plan
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Appendix A
The 12-Item Short Form Health Survey (SF-12)
Eight sub-scores are derived from the 12-item short-form survey (SF-12) as follow: 
Sub-score
Items (I, BP, GH)
Formula
Physical Functioning
I2a, I2b
100*(I2a+I2b-2)/(6-2)
Role-Physical
I3a, I3b
100*(I3a+I3b-2)/(10-2)
Bodily Pain
I5
100*(6-I5-1)/(5-1)
General Health
I1
100*(6-I1-1)/(5-1)
Vitality
I6b
100*(6-I6b-1)/(5-1)
Social Functioning
I7
100*(I7-1)/(5-1)
Role-Emotional
I4a, I4b
100*(I4a+I4b-2)/(10-2)
Mental Health
I6a, I6c
100*(6-I6a+I6c-2)/(10-2)
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Statistical Analysis Plan
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CONFIDENTIAL
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
SI 
<0.8 × LLN
>1.2 × ULN
Hematocrit
SI
<0.8 × LLN
>1.2 × ULN
RBC count 
SI
<0.8 × LLN 
>1.2 × ULN
WBC count 
SI
<0.5 x LLN
>1.5 x ULN
Platelet Count
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
SI
--
>3x ULN
AST
SI
--
>3x ULN
GGT
SI
--
>ULN - 2.5 x ULN if baseline was 
normal; 2.0 - 2.5 x baseline if 
baseline was abnormal
Alkaline phosphatase
SI
--
>ULN - 2.5 x ULN if baseline was 
normal; 2.0 - 2.5 x baseline if 
baseline was abnormal
Total Bilibrubin
SI
--
>ULN - 1.5 x ULN if baseline was 
normal; > 1.0 - 1.5 x baseline if 
baseline was abnormal
Albumin
SI 
<30 g/L
--
Total protein
SI
<0.8x LLN
>1.2x ULN
Creatinine
SI
>177 mol/L
Blood urea nitrogen
SI
>10.7 mmol/L
Sodium
SI
<130 mmol/L
>150 mmol/L
Potassium
SI
<3.0 mmol/L
>5.5 mmol/L
Blucose
SI
<3 mmol/L
>10 mmol/L*
Chloride
SI
<75 mmol/L
>126 mmol/L
Calcium
SI
Corrected serum calcium of <LLN -
8.0 mg/dL; <LLN - 2.0 mmol/L; 
Ionized calcium <LLN - 1.0 mmol/L
Bicarbonate
SI 
<8.0 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.
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Statistical Analysis Plan
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CONFIDENTIAL
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
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CONFIDENTIAL
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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