Clinical trial NCT04557189
Conditions: Postoperative Nausea and Vomiting (PONV)
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2020-10-20; Completion date: 2022-03-21
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Some adults are at a higher risk of feeling sick (nausea) or being sick (vomiting) after they have surgery. In this study, these adults will have planned surgery. The main aim of this study is to learn if TAK-951 stops these adults from getting nausea or vomiting after surgery. This will be compared with another medicine called ondansetron. Another aim is to check for side effects from the study medicines.

Before surgery, the study doctor will check who can take part in this study. Those who can take part will be picked for either Treatment Group A or Treatment Group B by chance.

* Treatment Group A: Just before surgery, participants will receive a placebo slowly through a vein (infusion). Just before the end of the surgery, they will receive TAK-951 as an injection under the skin.
* Treatment Group B: Just before surgery, participants will receive ondansetron slowly through a vein (infusion). Just before the end of the surgery, they will receive a placebo as an injection under the skin. In this study, a placebo will look like TAK-951 but will not have any medicine in it.

Participants will not know which study medicines they received, or in which order, nor will their study doctors or surgeons. This is to help make sure the results are more reliable.

Participants will stay in the hospital for 24 hours after their surgery so that the study doctors can check for nausea and vomiting. The study doctors will also check for side effects from the study medicines.

Participants will visit the hospital for a check-up 14 days later.

Detailed description:
The drug being tested in this study is called TAK-951. TAK-951 is being tested for prophylaxis for postoperative nausea and vomiting in high-risk participants.

The study will enroll a maximum of 160 patients, to allow a sample size of up to approximately 100 participants who have received both doses of Double-blind study drug/matching placebo. Participants will be randomly assigned in a 1:1 ratio to either Treatment Group A or Treatment Group B which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Treatment Group A: Just before surgery, participants will receive a placebo slowly through a vein (infusion). Just before the end of the surgery, they will receive TAK-951 as an injection under the skin.
* Treatment Group B: Just before surgery, participants will receive ondansetron slowly through a vein (infusion). Just before the end of the surgery, they will receive a placebo as an injection under the skin. In this study, a placebo will look like TAK-951 but will not have any medicine in it.

This trial will be conducted in the United States. The overall time to participate in the study from the time of surgery to completion is approximately 14 days. Participants will make multiple visits to the clinic and will be contacted by telephone after receiving their last dose of the drug for a follow-up assessment.

Arms: arm 1: Participants received prophylaxis with ondansetron 4 mg, intravenously (IV) immediately before induction and TAK-951 placebo subcutaneously (SC) approximately 30 to 45 minutes before the end of surgery (wound closure). arm 2: Participants received prophylaxis with ondansetron placebo IV immediately before induction and TAK 951 4 mg, SC, approximately 30 to 45 minutes before the end of surgery (wound closure).
Interventions: intervention 1: TAK-951 intervention 2: Ondansetron intervention 3: Ondansetron Placebo intervention 4: TAK-951 Placebo
Intervention descriptions: intervention 1: TAK-951 SC injection intervention 2: Ondansetron IV injection intervention 3: Ondansetron placebo-matching IV injection intervention 4: TAK-951 placebo-matching SC injection

Protocol documents:
Prot_000.pdf: 
NCT Number:  NCT04557189
Title: A Randomized Double-Blind, Sponsor-Open, Double-Dummy, Proof of 
Concept Phase 2 Study to Evaluate the Efficacy and Safety of TAK-951 Versus 
Ondansetron in the Prophylaxis of Postoperative Nausea and Vomiting in High-Risk 
Subjects
Study Number: TAK-951_2001
Document Version and Date: Amendment 4 / 13 September 2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Clinical Study Protocol 


1.0 TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized Double-Blind, Sponsor-Open, Double-Dummy, Proof of Concept Phase 2 
Study to Evaluate the Efficacy and Safety of TAK-951 Versus Ondansetron in the 
Prophylaxis of Postoperative Nausea and Vomiting in High-Risk Subjects
TAK-951 Versus Ondansetron Prophylaxis for Postoperative Nausea and Vomiting in 
High-Risk Subjects
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Study Number:
TAK-951-2001
IND Number:
141732
EudraCT Number:
Not applicable
Compound:
TAK-951
Date:
13 September 2021
Version/Amendment 
Number:
4
Amendment History:
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
13 September 2021
Amendment 4
Substantial
Global
28 July 2021
Amendment 3
Substantial
Global
11 January 2021
Amendment 2
Substantial
Global
22 September 2020
Amendment 1
Substantial
Global
23 June 2020
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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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
Property of Takeda: For Non-Commercial Use On
U
o the
d States 
State
he Applicable Terms of Use
th
assigne
assign
ant guid
nt gu
he
Only and Subject to t


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
Electronic signatures are provided on the last page of this document.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
rdance
dance
olidate
lidat
ta priva
a priva
ument.
ument
a: For Non-Commercial Use Only and Su


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in 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 4 Summary of Changes
Protocol Amendment 4 Summary and Rationale:
This section describes changes in reference to the protocol incorporating Amendment 4. The 
primary reason for this amendment is to add additional samples for pharmacokinetic (PK) analysis 
to better assess TAK-951 PK profiling in subjects undergoing anesthesia.
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.
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale
1.
Section 9.1.13 PK, DNA measurements, and 
Immunogenicity Sample Collection and 
Analysis
Section 9.3.3 Hospital Discharge/Early 
Termination
Appendix A Schedule of Study Procedures
Table 9.c: Added 2
pharmacokinetic (PK)
samples from 10-18 hours
and 22-26 hours and an 
associated footnote.
Appendix A: Added an 
additional 22- to 26-hour 
PK sample that may 
coincide with discharge.
To better assess TAK-951 
PK profiling in subjects 
undergoing anesthesia.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Principal Investigator/Coordinating Investigator ......................................................19
3.3
List of Abbreviations ...............................................................................................20
3.4
Corporate Identification...........................................................................................21
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.1.1
Nonclinical Background ..................................................................................22
4.1.2
Clinical Background ........................................................................................24
4.2
Rationale for the Proposed Study.............................................................................25
4.3
Benefit/Risk Profile .................................................................................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................28
5.1
Objectives................................................................................................................28
5.1.1
Primary Objective............................................................................................28
5.1.2
Secondary Objectives ......................................................................................29
5.1.3
Exploratory Objective......................................................................................29
5.2
Endpoints.................................................................................................................29
5.2.1
Primary Endpoint.............................................................................................29
5.2.2
Secondary Endpoints .......................................................................................29
5.2.3
Exploratory Endpoints .....................................................................................30
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................30
6.1
Study Design ...........................................................................................................30
6.2
Justification for Study Design, Dose, and Endpoints ................................................35
6.3
Premature Termination or Suspension of Study or Study Site...................................36
6.3.1
Criteria for Premature Termination or Suspension of the Study........................36
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................37
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites..............................................................................37
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............37
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7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................38
7.3
Potential Drug Interactions.......................................................................................39
7.3.1
Synergistic Effect When Combined With Propranolol and Sevoflurane............39
7.4
Excluded Medications..............................................................................................40
7.5
Rescue Therapy .......................................................................................................40
7.6
Diet, Fluid, Activity Control ....................................................................................41
7.7
Criteria for Discontinuation or Withdrawal of a Subject...........................................41
7.8
Procedures for Discontinuation or Withdrawal of a Subject......................................42
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................42
8.1
Study Drug and Materials ........................................................................................42
8.1.1
Study Drugs.....................................................................................................42
8.1.1.1
TAK-951.................................................................................................43
8.1.1.2
Ondansetron ............................................................................................43
8.1.1.3
Placebo....................................................................................................43
8.1.2
Clinical Study Drug Labeling ..........................................................................43
8.1.3
Clinical Study Drug Inventory and Storage......................................................43
8.1.4
Dose and Regimen...........................................................................................43
8.1.5
Overdose .........................................................................................................44
8.2
Study Drug Assignment and Dispensing Procedures ................................................44
8.3
Randomization Code Creation and Storage..............................................................44
8.4
Study Drug Blind Maintenance................................................................................45
8.5
Unblinding Procedure..............................................................................................45
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................46
9.0
STUDY PLAN ..............................................................................................................47
9.1
Study Procedures.....................................................................................................47
9.1.1
Informed Consent Procedure............................................................................47
9.1.2
Demographics, Medical History, and Medication History Procedure................47
9.1.3
Physical Examination Procedure......................................................................48
9.1.4
Height, Weight, and BMI.................................................................................48
9.1.5
Vital Sign Procedure........................................................................................48
9.1.6
Efficacy/Patient Reported Outcomes Measurement..........................................49
9.1.6.1
Postsurgery Assessment of Nausea ..........................................................49
9.1.6.2
Emetic Events..........................................................................................49
9.1.7
Documentation of Concomitant Medications ...................................................49
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9.1.8
Documentation of Concurrent Medical Conditions...........................................49
9.1.9
Procedures for Clinical Laboratory Samples ....................................................49
9.1.10
Contraception and Pregnancy Avoidance Procedure ........................................51
9.1.10.1
Male Subjects and Their Female Partners ................................................51
9.1.10.2
Female Subjects and Their Male Partners ................................................51
9.1.10.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...............................................................................................51
9.1.10.4
General Guidance With Respect to the Avoidance of Pregnancy..............53
9.1.11
Pregnancy........................................................................................................54
9.1.12
ECG and Telemetry Procedure.........................................................................54
9.1.13
PK, DNA measurements, and Immunogenicity Sample Collection and 
Analysis...........................................................................................................54
9.1.13.1
Collection of Blood/Plasma/Serum ..........................................................54
9.1.13.2
Immunogenicity.......................................................................................55
9.1.13.3
DNA Measurements ................................................................................56
9.1.13.4
Bioanalytical Methods.............................................................................56
9.1.14
Documentation of Screen Failure.....................................................................56
9.1.15
Documentation of Randomization....................................................................57
9.2
Monitoring Subject Treatment Compliance..............................................................57
9.3
Schedule of Observations and Procedures................................................................57
9.3.1
Screening.........................................................................................................57
9.3.2
Day 1...............................................................................................................58
9.3.2.1
Before Surgery ........................................................................................58
9.3.2.2
During Surgery........................................................................................58
9.3.2.3
Postsurgery Observational Period ............................................................59
9.3.3
Hospital Discharge/Early Termination .............................................................59
9.3.4
Follow-up Visit................................................................................................59
9.3.5
Poststudy Care.................................................................................................60
9.4
Biological Sample Retention and Destruction ..........................................................60
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................60
10.1
Definitions...............................................................................................................60
10.1.1
PTEs................................................................................................................60
10.1.2
AEs .................................................................................................................60
10.1.3
Additional Points to Consider for PTEs and AEs .............................................60
10.1.4
SAEs ...............................................................................................................62
10.1.5
AEs of Special Interest.....................................................................................63
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10.1.6
Intensity of PTEs and AEs ...............................................................................63
10.1.7
Causality of AEs..............................................................................................64
10.1.8
Relationship to Study Procedures.....................................................................64
10.1.9
Start Date.........................................................................................................64
10.1.10 Stop Date.........................................................................................................64
10.1.11 Frequency........................................................................................................64
10.1.12 Action Concerning Study Drug........................................................................65
10.1.13 Outcome..........................................................................................................65
10.2
Procedures...............................................................................................................65
10.2.1
Collection and Reporting of AEs .....................................................................65
10.2.1.1
PTE and AE Collection Period.................................................................65
10.2.1.2
PTE and AE Reporting ............................................................................66
10.2.1.3
AEs of Special Interest ............................................................................66
10.2.2
Collection and Reporting of SAEs ...................................................................67
10.2.3
Reporting of Abnormal Liver Function Tests...................................................67
10.2.4
Management of Specific AEs...........................................................................68
10.2.4.1
Hypotension ............................................................................................68
10.2.4.2
Injection Site Reactions ...........................................................................68
10.2.4.3
Hypersensitivity.......................................................................................68
10.2.4.4
Sinus Tachycardia ...................................................................................68
10.2.4.5
Potential Drug Interaction........................................................................68
10.3
Follow-up of SAEs ..................................................................................................68
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities................69
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................69
11.1
External DMC .........................................................................................................69
12.0
DATA HANDLING AND RECORDKEEPING............................................................69
12.1
(e)CRFs ...................................................................................................................69
12.2
Record Retention .....................................................................................................70
13.0
STATISTICAL METHODS..........................................................................................70
13.1
Statistical and Analytical Plans ................................................................................70
13.1.1
Analysis Sets ...................................................................................................71
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................71
13.1.3
Efficacy Analysis.............................................................................................71
13.1.4
PK Analysis.....................................................................................................72
13.1.5
DNA Analysis .................................................................................................72
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13.1.6
Immunogenicity Analysis ................................................................................73
13.1.7
Safety Analysis................................................................................................73
13.1.7.1
AEs .........................................................................................................73
13.1.7.2
Clinical Evaluations.................................................................................73
13.2
Interim Analysis and Criteria for Early Termination ................................................73
13.3
Determination of Sample Size..................................................................................74
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
14.1
Monitoring Visits.....................................................................................................74
14.2
Protocol Deviations..................................................................................................75
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................75
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRBs ........................................................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................76
15.3
Subject Confidentiality ............................................................................................77
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................78
15.4.1
Publication and Disclosure...............................................................................78
15.4.2
Clinical Trial Registration................................................................................78
15.4.3
Clinical Trial Results Disclosure......................................................................78
15.5
Insurance and Compensation for Injury....................................................................79
16.0
REFERENCES..............................................................................................................80
17.0
APPENDICES...............................................................................................................82
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................44
Table 9.a
Clinical Laboratory Tests...................................................................................50
Table 9.b
Sample Collection for PK, DNA Measurements, and Immunogenicity 
Assessments.......................................................................................................55
Table 9.c
PK Sampling Time Windows.............................................................................55
Table 10.a
Takeda Medically Significant AE List................................................................63
Table 10.b
NCI CTCAE ......................................................................................................64
Table 17.a
Hepatic Investigation .........................................................................................94
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LIST OF IN-TEXT FIGURES
Figure 6.a
BP Criteria for TAK-951 or Matching TAK-951 Placebo Dosing.......................32
Figure 6.b
HR Criteria for TAK-951 or Matching TAK-951 Placebo Dosing......................33
Figure 6.c
Schematic of Study Design ................................................................................35
Figure 8.a
Unblinding Procedure for Subjects Ineligible to Receive TAK-951 or Matching 
TAK-951 Placebo ..............................................................................................46
Figure 17.a
Liver Test Abnormality Monitoring and Follow-up............................................93
Figure 17.b
Liver Test Abnormalities: Considerations for Study Drug Discontinuation.........95
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................82
Appendix B
Verbal Rating Scale (VRS) for Nausea...............................................................84
Appendix C
Emetic Events....................................................................................................85
Appendix D
Responsibilities of the Investigator.....................................................................86
Appendix E
Elements of the Subject Informed Consent.........................................................88
Appendix F
Investigator Consent to Use of Personal Information..........................................91
Appendix G
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up....92
Appendix H
Protocol History.................................................................................................96
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
TAK-951
Title of Protocol:
A Randomized Double-Blind, Sponsor-Open, 
Double-Dummy, Proof of Concept Phase 2 Study to Evaluate 
the Efficacy and Safety of TAK-951 Versus Ondansetron in 
the Prophylaxis of Postoperative Nausea and Vomiting in 
High-Risk Subjects
IND No.: 141732
EudraCT No.:
Not Applicable 
Study Number: TAK-951-2001
Phase: 2
Study Design:
This is a phase 2 randomized, double-blind, sponsor-open, double-dummy, active-controlled study designed to assess 
the efficacy of TAK-951 to prevent the development of postoperative nausea and vomiting (PONV) in high-risk 
subjects undergoing elective surgery under general anesthesia. The study will also assess the safety, immunogenicity, 
and tolerability of TAK-951 in subjects undergoing elective surgery under general anesthesia. This is a double-blind 
study; the investigator and subjects are blinded to treatment assignment. The study will be conducted sponsor-open. 
Sponsor discussions with investigators and within the study team will be conducted in a blinded manner (ie, no 
unblinded information will be communicated to blinded investigators, site staff or blinded study monitoring 
personnel).
Subjects will be screened for enrollment up to 28 days before surgery. To be enrolled into the study and randomized to 
study drug, subjects will be required to meet all inclusion criteria and none of the criteria for exclusion. On the day of 
surgery, eligible subjects with 3 or more PONV risk factors will be randomized to either Treatment Group A to receive 
ondansetron placebo intravenously ([IV] administered in not less than 30 seconds, preferably over 2 to 5 minutes) 
immediately before induction of anesthesia and prophylaxis with 4 mg TAK-951 subcutaneously (SC) approximately 
30 to 45 minutes before the end of surgery (defined as wound closure) or Treatment Group B to receive 4 mg 
ondansetron IV (administered in not less than 30 seconds, preferably over 2 to 5 minutes) immediately before 
induction of anesthesia and TAK-951 placebo SC approximately 30 to 45 minutes before the end of surgery. 
Study drugs will be dosed sequentially: ondansetron or matching ondansetron placebo prior to induction of anesthesia 
[ie, before surgery], and TAK-951 or matching TAK-951 placebo prior to wound closure [ie, during surgery]. After 
randomization to Treatment Group A or B, subjects must demonstrate eligibility based on heart rate (HR), blood 
pressure, and cardiovascular stability before administration of each dose of study drug; these postrandomization 
criteria for study drug treatment are in addition to exclusion criterion #14 (Section 7.2) which applies to subject 
eligibility for enrollment and randomization. For subjects who have been randomized but not yet received ondansetron 
or matching ondansetron placebo at induction, the vital sign requirements in exclusion criterion #14 are applicable 
before administration of ondansetron or matching ondansetron placebo (see Section 6.1 for details). Similarly, HR and 
blood pressure requirements must be met and cardiovascular stability demonstrated immediately before 
administration of TAK-951 or matching TAK-951 placebo. Specific criteria to determine eligibility for TAK-951 or 
matching TAK-951 placebo are detailed in Section 6.1. Subjects who do not receive the first dose of study drug (ie, 
ondansetron or matching ondansetron placebo) due to the vital sign requirements will be discontinued from the study. 
Subjects who do not receive the second dose of study drug (ie, TAK--951 or matching TAK-951 placebo) due to the 
vital sign requirements in Section 6.1 will be unblinded to the investigator; those who received placebo at induction of 
anesthesia as their first dose of study drug will be discontinued from the study, and those who received ondansetron 
will continue to be monitored and assessed to study completion per-protocol. The decision to hold either dose of study 
drug/matching placebo will be recorded in the electronic case report form.
Only subjects undergoing elective surgery under general anesthesia that is expected to last at least 1 hour from 
induction of anesthesia to wound closure are eligible to participate in the study. The anesthesia protocol will allow the 
use of premedication with midazolam or fentanyl. Induction will be accomplished with propofol. Nitrous oxide will 
not be permitted. Anesthesia will be maintained with either sevoflurane or desflurane but total intravenous anesthesia 
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or propofol infusions for maintenance of anesthesia will not be permitted. Neuromuscular blocking agents may be 
used at the discretion of the anesthesiologist. Reversal, if utilized, will be accomplished with neostigmine and 
glycopyrrolate. Intraoperative analgesia may be accomplished with fentanyl or sufentanil as indicated. 
Postoperatively, the analgesic regimen will be left to the discretion of the physician. Patient-controlled analgesia and 
analgesic adjuncts, such as nonsteroidal anti-inflammatory drugs and pregabalin, are allowed. Intraoperative steroids 
will not be permitted. 
Antiemetics, other than the study drugs, are prohibited within 24 hours before and up to 24 hours after surgery except 
for postoperative rescue therapy. Subjects having 1 or more episodes of vomiting, retching, or significant nausea, 
defined as nausea score ≥4 measured on a 0 to 10 verbal response scale (VRS) after surgery, (0 = no nausea at all and 
10 = the worst nausea imaginable) or upon subject’s request, will receive the recommended rescue therapy and will be 
considered a treatment failure. Treatment failures will be analyzed and reported at the 6 hour time point (meeting 
criteria above from time 0 to 6 hours) and at the 24-hour time point (meeting above criteria from time 0 to 24 hours).
Subjects will be monitored for the occurrence of emesis and the occurrence and severity of any nausea within the first 
24 hours after surgery. Emesis will be defined as vomiting, the forceful discharge of even the smallest amount of 
stomach contents; or retching defined as the same muscular actions as vomiting but without expulsion of stomach 
contents. Nausea will be defined as the urge to vomit without the presence of expulsive muscular movements. The 
severity of nausea will be recorded by the site staff using a subject-reported 0 to 10 VRS, where 0 represents no nausea 
and 10 represents the worst nausea imaginable at 30 minutes and 1, 2, 6, and 24 hours after completion of surgery 
(wound closure). Any spontaneous complaints of nausea by subjects will also be noted and assessed for severity.
Subjects may be discharged 24 hours after completion of surgery and all scheduled procedures before discharge. 
Subjects will attend the clinic for a follow-up visit on Day 14±2 for assessment of concomitant medications, adverse 
events (AEs), and blood sample for immunogenicity assessment.
An interim analysis may be conducted when approximately 50 subjects have received both doses of double-blind 
study drug/matching placebo before surgery and during surgery and then have either completed all study procedures 
or withdrawn from the study with the objective of conducting a futility analysis. Additional descriptive analysis for 
primary and selected secondary and/or exploratory efficacy endpoints may be performed for both treatment arms to 
aid the internal decision-making. Other additional interim analysis of safety and/or efficacy may be conducted and 
would be defined in the statistical analysis plan (SAP).
Primary Objective:
The primary objective of this study is to assess the efficacy of a single-dose of TAK-951 compared with ondansetron 
to prevent PONV in the immediate postoperative period (within 6 hours post surgery) in high-risk subjects undergoing 
elective surgery under general anesthesia.
Secondary Objectives:
The secondary objectives of this study are:
!
To assess the efficacy of TAK-951 to prevent PONV up to 24 hours post surgery compared with ondansetron.
!
To assess the pharmacokinetics (PK) of TAK-951 in subjects undergoing elective surgery under general 
anesthesia.
!
To assess the safety, immunogenicity, and tolerability of TAK-951 in subjects undergoing elective surgery under 
general anesthesia.
Exploratory Objective:
The exploratory objective of this study is:
surgery and subjects requiring rescue therapy for breakthrough PONV within 3 and 6 hours post surgery.
Subject Population: Subjects aged ≥18 years with 3 or more risk factors for PONV undergoing elective surgery 
under general anesthesia.
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TAK-951
Study No. TAK-951-2001
Page 14 of 108
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CONFIDENTIAL
Number of Subjects:
Allow a sample size of up to approximately 100 subjects who 
have received both doses of double-blind study drug/matching 
placebo dosed per protocol as:

Ondansetron 4 mg: ~50 - 70 subjects

4 mg TAK-951: ~50 subjects
A maximum of 160 subjects will be randomized in this study.
Number of Sites: 
Estimated total: 10 sites in the United States
Dose Levels:
Group A:

Prophylaxis with ondansetron placebo IV immediately 
before induction and 4 mg TAK-951 SC approximately 
30 to 45 minutes before the end of surgery (wound 
closure). 
Route of Administration:

4 mg TAK-951: SC

Ondansetron placebo: IV
Group B:

Prophylaxis with 4 mg ondansetron IV immediately 
before induction and TAK-951 placebo SC 
approximately 30 to 45 minutes before the end of surgery 
(wound closure).

4 mg ondansetron: IV 

TAK-951 placebo: SC
Duration of Treatment:
Up to 24 hours
Period of Evaluation:
14±2 days after TAK-951 dose
Main Criteria for Inclusion: 
Subject eligibility is determined according to the following criteria before entry into the study:
1.
Male or female subjects aged ≥18 years at screening. 
2.
Subjects undergoing elective surgery under general anesthesia, expected to last for at least 1 hour from induction 
of anesthesia to wound closure.
3.
Subject is expected to require, or has agreed to stay, at least 1 overnight in the hospital.
4.
The subject’s American Society of Anesthesiologist physical status is ASA I-III.
5.
Subjects with 3 or more Apfel risk factors: 
a)
Female sex.
b)
Nonsmoking (never smoked or stopped smoking ≥12 months ago).
c)
History of PONV or motion sickness.
d)
Planned use of postoperative opioid analgesics.
6.
Subjects of nonchildbearing potential or subjects of childbearing potential willing and agreeable to use highly 
effective contraception or sexual abstinence during the study and up to 30 days post treatment.
Main Criteria for Exclusion: 
1.
Subjects who are expected to remain intubated post anesthesia.
2.
Subjects who experience vomiting 24 hours before surgery or are diagnosed with gastroparesis, cyclic vomiting 
syndrome, or other condition associated with chronic nausea and vomiting.
3.
Subjects with a history of allergic reaction to, intolerances of, or contraindications for any of the study 
medications or required anesthetic agents, including any component of the formulation of ondansetron or 
TAK-951. 
4.
Subjects who have received, or are expected to receive, any excluded drug preoperatively within 24 hours before 
induction, during surgery, or within 24 hours after surgery.
5.
Subjects scheduled to receive neuraxial anesthesia (eg, epidural, spinal, or caudal anesthesia), regional blocks, or 
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TAK-951
Study No. TAK-951-2001
Page 15 of 108
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CONFIDENTIAL
total IV anesthesia, and/or has planned to receive different drugs for premedication, induction, maintenance, or 
reversal of anesthesia than those specified in the protocol. 
6.
Subjects who have an allergy or contraindication to the recommended and available rescue therapy for treatment 
of PONV.
7.
Subjects expected to require the use of a nasogastric or oral gastric tube after surgery.
8.
Female subjects who are pregnant or lactating.
9.
Subjects with documented history of alcohol and/or drug abuse within 1 year of study medication.
10. Subjects who have any other significant, uncontrolled organic or systemic medical condition or social 
circumstance that, in the investigator’s opinion, make participation in this clinical study inappropriate.
11. Subjects found at screening to have a QTcF (QT interval with Fridericia correction method) interval ≥450 msec or 
other factors that increase the risk of QT prolongation or arrhythmic events. Assessments showing bundle branch 
block and a prolonged QTcF should be discussed with the study monitor and the sponsor for potential inclusion.
12. Subjects who have direct family history of premature sudden death or channelopathy, personal history of Brugada 
syndrome (right bundle branch block pattern with ST elevation in leads V1-V3), long QT, short QT, 
arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy or catecholaminergic polymorphic 
ventricular tachycardia (VT).
13. Subjects who have had 3 incidents of vasovagal syncope within the last 5 years. 
14. Subjects with an average HR <55 or >100 bpm or a systolic blood pressure <90 mm Hg or diastolic blood pressure 
<60 mm Hg during screening or prior to randomization on the day of surgery. 
Note: Vital sign criteria must be met postrandomization, before administration of ondansetron or matching 
ondansetron placebo and as gating criteria before administration of TAK-951 or matching TAK-951 placebo (see 
Section 6.1 for details). Subjects who exhibit signs suggestive of cardiovascular instability (as evaluated by the 
anesthesiologist) before administration of either dose of study drug/matching placebo should not be dosed, and 
the corresponding decision should be recorded. 
15. Subjects with a clinically significant electrocardiogram (ECG) abnormality indicative of acute cardiac instability 
as determined by the investigator at screening, including more than first degree atrioventricular block, 
nonsustained or sustained VT, or ECG changes consistent with acute myocardial ischemia or infarction. 
16. Subjects with a history of acute myocardial ischemia within the last 12 months.
17. Subjects receiving beta blockers chronically or between screening and surgery that cannot be safely withheld on 
the day of surgery in the investigator’s judgment. Subjects receiving certain other cardiovascular medications, 
such as vasodilators for hypertension, chronically or between screening and surgery that in the investigator’s 
judgment cannot be adequately managed in the perioperative setting considering the potential vasodilator effects 
of TAK-951 and anesthesia standard of care. The investigators must consult with the medical monitor regarding 
eligibility of subjects who are receiving beta blockers, vasodilators, and other classes of medications that act on 
HR or blood pressure.
18. Subjects with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of 
normal (ULN) or total bilirubin >1.5 times the ULN.
19. Subjects with known liver disease or positive for hepatitis B or C. For hepatitis B/C, the subject has 1 of the 
following at screening:

Chronic hepatitis B virus infection: positive for hepatitis B surface antigen (HBsAg). 

Chronic hepatitis C virus (HCV) infection: positive for HCV antibody that is confirmed with a positive HCV 
RNA viral load test (those treated and cured for HCV infection are allowed).
20. Subjects who have participated in an interventional clinical study or been exposed to any experimental drug 
within 30 days before enrollment of this study.
21. Subjects who are an immediate family member, study site employee, or 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.
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TAK-951
Study No. TAK-951-2001
Page 16 of 108
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CONFIDENTIAL
Main Criteria for Evaluation and Analyses:
Primary Endpoint:
The primary efficacy endpoint is complete response in the immediate postoperative period (6 hours post surgery), 
defined as no emesis (vomiting or retching) and no need for rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) (Yes/No).
Secondary Endpoints:
!
Complete response within 24 hours post surgery (Yes/No).
!
Emesis in the first 6 hours post surgery (Yes/No).
!
Emesis within 24 hours post surgery (Yes/No).
!
Absence of nausea in the first 6 hours post surgery (Yes/No).
!
Absence of nausea within 24 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 24 hours post surgery (Yes/No).
!
Time from end of surgery to first emetic event (vomiting or retching). 
!
Peak nausea VRS score (0 = no nausea at all, and 10 = the worst nausea imaginable) at 30 minutes and 1, 2, 6, and 
24 hours after completion of surgery in subjects who have not required rescue therapy.
!
Total response within 24 hours post surgery, defined as no emesis, no nausea (VRS <1), and no need for rescue 
therapy (Yes/No). 
!
TAK-951 individual plasma concentrations.
!
Safety:
–
AEs.
–
Vital signs.
–
ECG.
–
Laboratory values (hematology and chemistry). 
–
Immunogenicity assessment (positive/negative anti-drug antibody and titer).
Exploratory Endpoints
!
!
efined as no emesis (vomiting or retching) and no need 
for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or upon subject’s request) (Yes/No).
!
Emesis within the first 3 hours post surgery (Yes/No).
!
Absence of nausea within the first 3 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 3 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 6 hours post surgery (Yes/No).
Statistical Considerations
Analysis Sets: 
The Full Analysis Set (FAS) will include all subjects who were randomized to treatment and received both doses of 
double-blind study drug (ie, ondansetron or matching ondansetron placebo, and TAK-951 or matching TAK-951 
placebo) before surgery and during surgery. Subjects will be analyzed according to their randomized treatment, 
regardless of whether they receive an investigational product that is different from that to which they were 
randomized. 
The Per-Protocol Analysis Set (PPAS) will include all subjects who are in the FAS and do not violate the terms of the 
protocol in a way that would impact the study output significantly. All decisions to exclude subjects for the 
per-protocol population will be made before the unblinding of the study. Analyses using the PPAS will be provided as 
a sensitivity analysis.
The Safety Analysis Set will include all subjects who were randomized to treatment and received both doses of 
double-blind study drug (ie, ondansetron or matching ondansetron placebo, and TAK-951 or matching TAK-951 
placebo) before surgery and during surgery. In safety summaries, subjects will be analyzed according to the treatment 
they actually received. 
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TAK-951
Study No. TAK-951-2001
Page 17 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
The PK Analysis Set will consist of all subjects who receive study drug and have at least 1 evaluable PK sample. 
Efficacy Analysis:
The primary and secondary efficacy analyses and summaries will be based on the FAS. Sensitivity analyses will be 
conducted for the primary and secondary efficacy endpoints using the PPAS. To evaluate the impact of the identified 
dosing error at some participating sites, additional sensitivity analysis may be performed in the Safety Analysis Set by 
the actual treatment received.
Primary Efficacy Analysis: The primary efficacy analysis will be comprised of estimation of the treatment difference 
with respect to the primary efficacy endpoint. The proportions of complete responders 6 hours post surgery in the 
TAK-951 and ondansetron groups, along with the treatment difference in proportions, will be estimated along with the 
associated 2-sided 80% and 95% confidence intervals (CIs). The point estimate of the treatment difference between 
TAK-951 and ondansetron and the associated CIs will be based on the Cochran-Mantel-Haenszel method adjusting for 
the number of Apfel risk factors. In the event that the number of responders or non-responders in either treatment 
group is too small (ie, ≤5), the exact method (eg, Clopper-Pearson CI for proportions in each treatment group and 
exact unconditional confidence limits for treatment difference) will be performed instead. Subjects who are missing 
data needed to determine endpoint status will be considered as treatment failures (non-responder imputation).
Subgroup analyses by the number of simplified Apfel risk factors (3 or 4) and postoperative opioid analgesics opioid 
usage (yes or no) for the primary endpoint will be performed using the statistical methods used for the primary efficacy 
analysis. Point estimates and the associated 80% CI and 95% CI for the true treatment difference between TAK-951 
and ondansetron will be presented for the subgroups.
Secondary Efficacy Analysis: The binary secondary endpoints include: emesis in the first 6 hours and within 24 hours 
post surgery, absence of nausea in the first 6 hours and within 24 hours post surgery, requiring rescue therapy for 
breakthrough PONV within 24 hours post surgery, and total response within 24 hours post surgery, will be analyzed 
similarly to the primary efficacy endpoint. The peak nausea VRS score at 30 minutes and 1, 2, 6, and 24 hours after 
completion of surgery in subjects will be analyzed using a mixed-effect model repeated measures (MMRM). This 
MMRM model will include treatment, the number of Apfel risk factors, timepoint, and treatment-by-timepoint 
interaction as fixed effects, and subject as a random effect. Point estimates and the associated 80% and 95% CIs for 
treatment difference between TAK-951 and ondansetron by timepoint will be presented. The time from the end of 
surgery to the first emetic event endpoints will be analyzed using the Cox proportional hazards model. Point estimate 
and the associated 80% and 95% CIs for the hazard ratio for TAK-951 versus ondansetron will be provided.
Safety Analysis: Safety data being collected in a double-blinded fashion will be summarized using the Safety Analysis 
Set and will include AEs, clinical safety laboratory tests, vital signs, ECG parameters, and weight. Subjects who are 
ineligible to receive the second dose of study drug (ie, TAK-951 or matching TAK-951 placebo) due to failure to meet 
the vital sign requirements outlined in Section 6.1 will be unblinded to the investigator; their safety data collected will 
be summarized separately.
Interim Analysis:
An interim analysis for futility based on the primary efficacy endpoint may be conducted based on Bayesian predictive 
probability after approximately 50 subjects have received both doses of double-blind study drug/matching placebo 
before surgery and during surgery and then have either completed all study procedures or withdrawn from the study. 
The study may be stopped if the Bayesian predictive probability calculated based on the interim TAK-951 primary 
endpoint data meets the prespecified stopping rule criteria for futility; otherwise, the study will continue as planned in 
the absence of safety concerns. Futility is nonbinding. Additional descriptive analysis for primary and selected 
secondary and/or exploratory efficacy endpoints may be performed for both treatment arms to aid the internal 
decision-making. Other additional interim analysis of safety and/or efficacy may be conducted and would be defined 
in the SAP.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study No. TAK-951-2001
Page 18 of 108
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13 September 2021
CONFIDENTIAL
Sample Size Justification:
The sample size was calculated based on primary efficacy analysis (ie, estimation of treatment difference with respect 
to the primary efficacy endpoint). Assuming true complete response rates at 6 hours of 60% and 80% in the 
ondansetron and TAK-951 groups respectively, given approximately 50 subjects per treatment group, the half width of 
a 2-sided 80% CI and a 2-sided 95% CI for treatment difference between TAK-951 and ondansetron in primary 
efficacy endpoint complete response rate at 6 hours will be approximately 11.5% and 17.5%, respectively, based on 
CIs using the normal approximation for the binomial distribution. This level of precision with the chosen sample size 
was considered acceptable for the statistical objective of this trial. 
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TAK-951
Study No. TAK-951-2001
Page 19 of 108
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CONFIDENTIAL
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 
study-related responsibilities template. 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 
Takeda 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 drug used in the study, 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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TAK-951
Study No. TAK-951-2001
Page 20 of 108
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CONFIDENTIAL
3.3
List of Abbreviations
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CBL
change from baseline
COVID-19
coronavirus disease 2019
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
ECG
electrocardiogram
(e)CRF
(electronic) case report form
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B virus surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HR
heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
MAP
mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measures
MRD
multiple rising dose
Property of Takeda: For Non-Comm
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IV
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TAK-951
Study No. TAK-951-2001
Page 21 of 108
Protocol Incorporating Amendment No. 4
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CONFIDENTIAL
NSVT
nonsustained ventricular tachycardia
PACU
postanesthesia care unit
PD
pharmacodynamic
PK
pharmacokinetic
PONV
postoperative nausea and vomiting
PPAS
Per-Protocol Analysis Set
PTE
pretreatment event
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
tmax
time to maximum plasma concentration
ULN
upper limit of normal
USPI
United States Prescribing Information
VRS
verbal rating scale
V,ss
volume of distribution at steady state after intravenous administration 
VT
ventricular tachycardia
WOCBP
women of childbearing potential
3.4
Corporate Identification
TDC Americas
Takeda Development Center Americas, Inc.
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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TAK-951
Study No. TAK-951-2001
Page 22 of 108
Protocol Incorporating Amendment No. 4
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CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
The term postoperative nausea and vomiting (PONV) is used to define any nausea, vomiting, or 
retching occurring in the immediate postoperative period. The mechanism leading to PONV is 
complex and seems to involve multiple emetic pathways. The incidence of PONV varies from 30% 
of all surgical patients to up to 80% of high-risk patients [1]. Some of the most relevant risk factors 
for PONV are not always modifiable as they are inherent patient characteristics (female sex, 
nonsmoking status, prior history of PONV, and history of motion sickness). Other proven risk 
factors are related to the use of volatile agents or nitric oxide as anesthetics, intraoperative and 
postoperative use of opioid, and duration of anesthesia/surgery. Certain types of procedures such 
as gynecologic; ophthalmic; ear, nose, and throat (ENT); or thyroid surgeries have also been 
described to be associated with an increased risk of PONV, though this risk has not been 
confirmed in large prospective trials [2]. The Simplified Apfel Risk Score includes the 4 most 
relevant risk factors for PONV (female sex, history of PONV and/or of motion sickness, 
nonsmoking status, and postoperative use of opioids) that is currently used in clinical practice and 
research as a simple tool to identify subjects at higher risk of PONV. Results from an international 
study including 2722 subjects undergoing surgery confirmed that each of the risk factors included 
in the Apfel Risk Score increases the risk of PONV by 20% [1].
4.1.1
Nonclinical Background
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-951
Study No. TAK-951-2001
Page 23 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Administration of the beta-blocker propranolol to dogs before TAK-951 administration resulted in 
a smaller HR increase than was seen with TAK-951 alone, while the combination of both 
propranolol and TAK-951 resulted in a greater decrease in blood pressure (BP) compared with that 
seen following administration of either treatment alone. 
TAK-951 administration to sevoflurane-anesthetized dogs resulted in decreases in systolic blood 
pressure (SBP) and diastolic blood pressure (DBP) immediately following dosing, which were 
maximal within 10 minutes postdose and partially recovered but remained decreased relative to 
predose levels up to 1 hour postdose, with a similar magnitude of change at all doses. There was a 
minimal increase in heart rate (HR) noted within 15 minutes postdose that remained through the 
anesthesia monitoring. Following recovery from the anesthesia and return to their home cage, 
there was a decrease in SBP and DBP with marked increases in HR noted for the remainder of the 
monitoring. The magnitude of the SBP, DBP, and HR changes in the conscious animals were 
generally dose related. Additional details are presented in the IB (edition 05).
In safety pharmacology studies, no adverse effects of TAK-951 were identified in the central 
nervous and respiratory systems in Good Laboratory Practice (GLP)-compliant studies in rats. 
TAK-951 was not a significant inhibitor of the human ether à-go-go–related gene (hERG) channel, 
the human sodium channel hNav1.5, human L-type calcium channel hCav1.2, or human 
hyperpolarization-activated, cyclic nucleotide-gated channel 4 (hHCN4) in vitro. Cardiovascular 
(CV) assessments were conducted through a series of non-GLP- and GLP-compliant safety
pharmacology studies in dogs using implanted telemetry. Administration of TAK-951 resulted in 
an increase in HR and a decrease in both SBP and DBP, among other changes in CV parameters. 
These effects were observed at all doses evaluated, and therefore the lowest dose was the 
lowest-observed-effect-level for CV changes. The use of individualized QT correction 
demonstrated TAK 951 had either no effect, or a minor (5 ms) effect on the corrected QT interval 
(QTc) interval. Fasting status did not affect TAK-951-related changes in HR, SBP, or DBP.
 
The plasma PK of TAK-951 was characterized in rats, dogs, minipigs, and monkeys with high 
clearance and moderate volume of distribution at steady state after intravenous administration (Vss) 
in rats, low clearance and low to moderate Vss in dogs and minipigs, and low clearance and Vss in 
monkeys and moderate to high bioavailability; good absorption; and a time to maximum plasma 
concentration (tmax) in the range of 0.33 to 1.67 hours (indicating rapid absorption) in rats, dogs, 
minipigs, and monkeys. 
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TAK-951
Study No. TAK-951-2001
Page 24 of 108
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CONFIDENTIAL
Repeat-dose subcutaneous (SC) administration of TAK-951 to rats and dogs for up to 14 days in 
duration was well tolerated. The only notable toxicity was injection site reactions, which generally 
recovered within 1 week. This observation of injection site reaction suggests that TAK-951 may 
have irritant properties when administered by SC injection to the same site for 7 consecutive days. 
Additionally, in rats there was a minimal TAK-951–related finding in eosinophil count that had no 
corresponding microscopic changes. 
4.1.2
Clinical Background
A recently completed single-rising dose (SRD) and multiple rising dose (MRD) phase 1 
first-in-human (FIH) study (TAK-951-1001) provided characterization of the single-dose and 
multiple-dose PK at multiple dose levels as well as the safety and tolerability profile of 
 TAK-951. This current phase 2 study will 
 test the 
antiemetic/antinausea mechanism 
 in humans. 
Following single SC dose administration, TAK-951 was readily absorbed with median tmax across 
the dose groups ranging from 1.03 to 2.08 hours and mean apparent terminal half-life across the 
dose groups ranging from 2.54 to 6.40 hours. Following multiple SC twice-daily dose 
administration 8 hours apart, TAK-951 was readily absorbed with median tmax across the dose 
groups ranging from 1.00 to 2.03 hours after the first dose on Days 1 and 5 and mean apparent 
terminal-half-life across the dose groups ranging from 3.89 to 4.86 hours on Day 5.
Of a total 96 subjects randomized in the SRD portion of the TAK-951-1001 study, 72 (75%) 
subjects received active study drug (TAK-951) and 24 (25%) subjects received placebo. Overall, 
33 (34.4%) subjects reported a total of 50 treatment-emergent adverse events (TEAEs): 29 
subjects (40.3%) in the TAK-951 group and 4 (17%) in the placebo group. Of the 29 subjects in the 
TAK-951 group, 23 (79%) subjects reported a TEAE related to TAK-951; 27 (93%) subjects 
reported Grade 1, and 2 (7%) subjects reported Grade 3 events. There were 4 subjects reporting 
grade 1 events in the placebo group. The most commonly reported (≥3 subjects) TEAEs were 
palpitations (6), dizziness postural (5), dizziness (4), postural orthostatic tachycardia syndrome, 
back pain, and orthostatic hypotension (3 each).
Safety results from the FIH study demonstrated a transient increase in HR within the first hour of 
TAK-951 dosing as well as decreases in SBP and DBP that were more prominent with postural 
changes (orthostatic) in some individuals within the first 2 hours post dosing. In semirecumbent 
position, the largest mean change from baseline (CBL) in SBP and DBP was -25 and -15 mm Hg 
in the TAK-951 
 cohorts, compared with -2.3 and 1.0 mm Hg in the placebo group 
at the same timepoint. In orthostatic position, the largest mean CBL in SBP and DBP was -10.3 
and 4 mm Hg in the TAK-951 
 cohort compared with 4.0 and -5 mm Hg in the placebo 
group. In semirecumbent position, the largest mean CBL in HR was 31 bpm in the TAK-951
 
cohort compared with -6.0 bpm in the placebo group. In orthostatic position, the largest mean 
CBL in HR was 34 bpm in the TAK-951
 cohort compared with 15 bpm in the placebo 
group.
Of a total 32 subjects randomized in the MRD portion of the TAK-951-1001 study, 24 subjects
received active study drug (TAK-951) and 8 subjects received placebo. A higher percentage of 
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TAK-951
Study No. TAK-951-2001
Page 25 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
subjects in the overall TAK-951 group (62.5%) compared with the pooled placebo group (37.5%) 
had TEAEs. In the pooled placebo group, 3 of 8 (37.5%) subjects had TEAEs; all 3 events were 
considered mild, and 1 was considered related to the study drug. In the overall TAK-951 group, 15 
of 24 (62.5%) subjects had TEAEs. Eleven subjects reported Grade 1 TEAEs, three reported 
Grade 2 TEAEs, and one reported a Grade 3 event. One SAE of ventricular tachycardia was 
reported in a subject in the 
TAK-951 cohort. Eleven (45.8%) subjects reported TEAEs that 
were considered related to the study drug. No subjects had an AE leading to study drug 
discontinuation, and no subjects died. Refer to the most recent version of the TAK-951 IB for 
detailed safety results including summarization of vital sign changes.
There was 1 SAE, nonsustained ventricular tachycardia (NSVT), in the MRD portion of the 
TAK-951-1001 study. The subject 
experienced the event approximately 5 hours 
and 23 minutes after receiving the first dose of TAK-951/placebo (tmax on Day 1 typically ranged 
from 0.5 to 2 hours). The subject was asymptomatic at the time of the event and continued to 
receive a total of 10 doses as planned. The additional doses were well tolerated, with no additional 
AEs or additional episodes of ventricular arrhythmias reported. Based on a literature review of the 
prevalence of background NSVT rates in the general population as well as the time course of the 
event [6,7], the sponsor was unable to confirm causality or rule out a direct effect of the study drug 
as the cause of this event.
4.2
Rationale for the Proposed Study
PONV is one of the main causes of patients’ dissatisfaction after anesthesia/surgery [8]; it may 
delay discharge from the hospital and can lead to serious complications, such as wound dehiscence, 
dehydration, electrolyte imbalance, esophageal tears, and aspiration of gastric content [9]. The 
physiopathology of PONV is complex and involves different pathways and receptors. Therefore, 
current guidelines recommend use of a combination of antiemetics with different mechanisms of 
action for subjects at high risk for PONV [9]. Data from an interventional study conducted in more 
than 5000 subjects given none, 1, 2, or 3 antiemetics suggested a simple additive rather than 
synergistic relationship between 5-HT3 antagonists, dopamine antagonists, and corticosteroid 
antiemetics, with each of these agents decreasing the relative risk of PONV by about 25%. This 
finding has been later corroborated in numerous combination prophylaxis studies [10,11].
This study is being conducted to assess the efficacy of TAK-951 in preventing PONV in high-risk 
subjects undergoing elective surgery under general anesthesia.
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TAK-951
Study No. TAK-951-2001
Page 26 of 108
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4.3
Benefit/Risk Profile
Based on nonclinical findings from studies conducted with TAK-951, and given the compound’s 
proposed mechanism of action, the anticipated potential benefits of TAK-951 include effective 
treatment of nausea and vomitin
 If the nonclinical data are confirmed in humans, 
patients at high-risk of PONV may demonstrate a decreased incidence of PONV when treated 
prophylactically with TAK-951. Note, that patients will be continuously monitored and will
receive appropriate rescue therapy (standard of care), which will be available upon request, in case 
of lack of therapeutic response. 
 and decreased BP 
 and a 
proposed mechanism of vasodilation (refer to IB Section 6.4.1), it is hypothesized that TAK-951 
causes vasodilation, which leads to decreased blood pressure and tachycardia.
TAK-951 administration to sevoflurane-anesthetized dogs resulted in decreases in systemic BP 
(including SBP and DBP) immediately following dosing, which were maximal within 10 minutes 
postdose and partially recovered, but remained decreased relative to predose levels up to 1 hour 
postdose, with a similar magnitude of change at all doses. There was a minimal increase in HR 
noted within 15 minutes postdose that remained through the anesthesia monitoring. Following 
recovery from the anesthesia and return to their home cage, there was a decrease in systemic BP 
(including SBP and DBP) with marked increases in HR noted for the remainder of the monitoring. 
The magnitude of the BP and HR changes in the conscious animals were generally dose related. 
The observed transient drops in SBP and DBP may be consistent with a possible vasodilatory
mechanism of TAK-951, which should be taken into account when TAK-951 is coadministered in 
an acute care setting with other agents that have potential cardiovascular effects.
Based on the completed TAK-951 FIH study, 2 ongoing TAK-951 studies, nonclinical studies 
conducted with TAK-951, 
 potential risks of TAK-951 include HR increase, decreased BP, and synergistic effect 
when combined with beta blockers, injection site reactions, and immunogenicity. Based on the 
data from the FIH study, effects on 
 are no longer considered 
as a potential risk.
Safety results from the FIH study demonstrated a transient increase in HR within the first hour of 
TAK-951 dosing as well as decreases in SBP and DBP that were more prominent with postural 
changes (orthostatic) in some individuals within the first 2 hours post dosing. The preliminary
exposure-response analysis suggests a trend in increase in HR and decrease in DBP with increase 
in exposure at lower range but plateaus at higher exposure. Postural hypotension (<20 mm Hg in 
SBP or <10 mm Hg DBP within 3 minutes of standing) is considered an identified risk. In SRD, 
after receiving TAK-951, 3 subjects (4.2%) experienced orthostatic hypotension, including 
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TAK-951
Study No. TAK-951-2001
Page 27 of 108
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CONFIDENTIAL
1 subject with a Grade 3 event, and 5 subjects (6.9%) experienced postural dizziness, all Grade 1 
in severity. In MRD, after receiving TAK-951, 2 subjects (8.3%) experienced orthostatic 
hypotension, both Grade 2 in severity, and 2 subjects (8.3%) experienced postural dizziness; 
Grade 1 in severity. Following the third dose on Day 2, there was no observed trend in HR after 
TAK-951 administration, suggesting an attenuation of effects on HR (IB edition 05).
The risks listed in the prescribing information associated with ondansetron include 
hypersensitivity reactions including anaphylaxis and bronchospasm, QT prolongation, torsades de 
pointe, and serotonin syndrome.
The risks listed in the prescribing information with midazolam, which will be used as anesthesia in 
the current study, include serious cardiorespiratory events and possible paradoxical reactions. 
Fluctuations in vital signs are the most frequently seen findings following parenteral 
administration of midazolam in adults; these fluctuations include decreased tidal volume and/or 
respiratory rate, apnea, and variations in BP and pulse rate. Administration of intramuscular 
midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with 
rare reports of death under circumstances compatible with cardiorespiratory depression.
The risks listed in the prescribing information associated with fentanyl, which will be used as 
anesthesia, include life-threatening respiratory depression, severe cardiovascular depression, 
serotonin syndrome, seizures, gastrointestinal adverse reactions, and drug interactions. 
The risks listed in the prescribing information associated with propofol, which will be used as an 
inducing agent, include cardiorespiratory effects and risk of metabolic derangements and organ 
system failures, referred to as propofol infusion syndrome.
The most frequently reported risks during maintenance of anesthesia with sevoflurane are 
hypotension, followed by tachypnea, muscle tenseness, excitation, apnea, muscle fasciculations 
and emesis. The most frequently risks during maintenance of anesthesia with desflurane include 
headache, bradycardia, hypertension, nodal arrhythmia, tachycardia, nausea, vomiting, increased 
salivation, apnea, cough, laryngospasm, pharyngitis, and conjunctivitis.
To manage the risks to the subjects in this study, the following mitigations will be implemented:
1. Subjects with a history of serious hypersensitivity to any medication or any component of 
TAK-951 formulation or ondansetron, as well as those with a history of significant multiple 
and/or severe allergies, are excluded from this study. 
2. Subjects will be excluded for HR <55 or >100 bpm and hypotension (defined as SBP <90 mm 
Hg or DBP <60 mm Hg) during screening and prior to randomization on the day of surgery.
3. TAK-951 or matching TAK-951 placebo will not be administered if there are signs suggestive 
of cardiovascular instability during surgery (as evaluated by the anesthesiologist). Specific HR 
and BP criteria must be met immediately prior to TAK-951 or matching TAK-951 placebo 
dosing as detailed in Section 6.1 to avoid administration of TAK-951 in subjects whose 
predose vital signs meet the criteria for low (or borderline low) BP, bradycardia, or 
tachycardia.
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TAK-951
Study No. TAK-951-2001
Page 28 of 108
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CONFIDENTIAL
4. Subjects whose QT interval with Fridericia correction method (QTcF) is ≥450 msec or those 
with other factors that increase the risk of QT prolongation or arrhythmic events will be 
excluded.
5. Vital signs (HR and BP) will be collected in duplicate and averaged at all time points. Vital 
signs will be collected at screening, before dosing with ondansetron or matching ondansetron 
placebo (ie, before surgery), immediately before dosing with TAK-951 or matching TAK-951 
placebo (ie, during surgery), and at the end of surgery (defined as wound closure) and recorded 
in the electronic case report form ([e]CRF). During surgery, vital signs will be monitored 
continuously for safety purposes. During the immediate postsurgical period, vital signs will be 
monitored upon admittance to the postanesthesia care unit (PACU) and collected every 
15 minutes until 1 hour post surgery, then every 30 minutes until 4 hours post surgery, then 
every hour until 8 hours post surgery, then every 6 hours until 24 hours post surgery, and again 
at discharge.
6. ECGs will be monitored continuously by telemetry during surgery and for the first 24 hours 
post surgery. A standard 12-lead ECG will be performed at screening, on Day 1 before surgery, 
on admittance to the PACU (approximately 1 hour post dose), and before hospital discharge. In 
case of symptoms (palpitations or dizziness) or if abnormalities are identified on telemetry, a 
12-lead ECG will be performed.
7. Detailed guidance is provided to the investigator (Section 10.2.4 Management of Specific AEs) 
for management of potential risk of increased HR and decreased BP related to TAK-951.
8. Administration of study drug must occur in a controlled environment to ensure close 
monitoring of subjects by the anesthesiologist and access to appropriate rescue medications.
9. Well-defined study stopping rules are provided that take into consideration the possible risk of 
increased HR and decreased BP.
10. An external Data Monitoring Committee (DMC) will be utilized for safeguarding the interest 
of study participants and assessing safety while maintaining the integrity of the study. The 
DMC will meet on a periodic basis during the conduct of the study as well as ad hoc for any 
safety concerns or in case any one of the stopping criteria are met.
Subjects will be evaluated for the development of antidrug antibodies (ADA) as part of the study. 
Overall, the current mitigation strategies have been deemed adequate to monitor the safety of the 
subjects participating in the study.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to assess the efficacy of a single-dose of TAK-951 compared 
with ondansetron to prevent PONV in the immediate postoperative period (within 6 hours post 
surgery) in high-risk subjects undergoing elective surgery under general anesthesia.
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TAK-951
Study No. TAK-951-2001
Page 29 of 108
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5.1.2
Secondary Objectives
The secondary objectives of this study are:
!
To assess the efficacy of TAK-951 to prevent PONV up to 24 hours post surgery compared 
with ondansetron.
!
To assess the PK of TAK-951 in subjects undergoing elective surgery under general 
anesthesia.
!
To assess the safety, immunogenicity, and tolerability of TAK-951 in subjects undergoing 
elective surgery under general anesthesia.
5.1.3
Exploratory Objective
The exploratory objective of this study is:
!
To assess the binary responses of complete response, emesis, and absence of nausea within the 
first 3 hours post surgery and subjects requiring rescue therapy for breakthrough PONV within 
3 and 6 hours post surgery.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary efficacy endpoint is complete response in the immediate postoperative period 
(6 hours post surgery), defined as no emesis (vomiting or retching) and no need for rescue therapy 
(indicated if vomiting/retching and/or nausea score ≥4 or upon subject’s request) (Yes/No).
5.2.2
Secondary Endpoints 
!
Complete response within 24 hours post surgery (Yes/No).
!
Emesis in the first 6 hours post surgery (Yes/No).
!
Emesis within 24 hours post surgery (Yes/No).
!
Absence of nausea in the first 6 hours post surgery (Yes/No).
!
Absence of nausea within 24 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 24 hours post surgery (Yes/No).
!
Time from end of surgery to first emetic event (vomiting or retching). 
!
Peak nausea verbal rating scale (VRS) score (0 = no nausea at all, and 10 = the worst nausea 
possible) at 30 minutes and 1, 2, 6, and 24 hours after completion of surgery in subjects who 
have not required rescue therapy.
Property of Takeda: For Non-Commercial Use Only and Subje
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TAK-951
Study No. TAK-951-2001
Page 30 of 108
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!
Total response within 24 hours post surgery, defined as no emesis, no nausea (VRS <1), and no 
need for rescue therapy (Yes/No). 
!
TAK-951 individual plasma concentrations.
!
Safety:
–
Adverse events (AEs).
–
Vital signs.
–
ECG.
–
Laboratory values (hematology and chemistry). 
–
Immunogenicity assessment (positive/negative ADA and titer).
5.2.3
Exploratory Endpoints
!
Complete response within the first 3 hours post surgery, defined as no emesis (vomiting or 
retching) and no need for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 
or upon subject’s request) (Yes/No).
!
Emesis within the first 3 hours post surgery (Yes/No).
!
Absence of nausea within the first 3 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 3 hours post surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 6 hours post surgery (Yes/No).
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 2 randomized, double-blind, sponsor-open, double-dummy, proof-of-concept study 
designed to assess the efficacy of TAK-951 compared with ondansetron in the prophylaxis of 
PONV in high-risk subjects undergoing elective surgery under general anesthesia. The study will 
also assess the safety, immunogenicity, and tolerability of TAK-951 in subjects undergoing 
elective surgery under general anesthesia. This is a double-blind study; the investigator and 
subjects are blinded to treatment assignment. The study will be conducted sponsor-open. Sponsor 
discussions with investigators and within the study team will be conducted in a blinded manner (ie, 
no unblinded information will be communicated to blinded investigators, site staff or blinded 
study monitoring personnel).
Subjects aged ≥18 years with 3 or more risk factors for PONV who are undergoing elective 
surgery under general anesthesia will be screened for enrollment up to 28 days before surgery. To 
be enrolled into the study and randomized to study drug, subjects will be required to meet all 
inclusion criteria and none of the criteria for exclusion. Antiemetics, other than the study drugs, are 
Property o
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TAK-951
Study No. TAK-951-2001
Page 31 of 108
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CONFIDENTIAL
prohibited within 24 hours before and up to 24 hours after surgery except for postoperative rescue 
therapy. Only subjects undergoing elective surgery under general anesthesia that is expected to last 
at least 1 hour from induction of anesthesia to wound closure are eligible to participate in the study. 
The anesthesia protocol will allow the use of premedication with midazolam or fentanyl. Induction 
will be accomplished with propofol. Nitrous oxide will not be permitted. Anesthesia will be 
maintained with either sevoflurane or desflurane, but total IV anesthesia or propofol infusions for 
maintenance of anesthesia will not be permitted. Neuromuscular blocking agents may be used at 
the discretion of the anesthesiologist. Reversal, if utilized, will be accomplished with neostigmine 
and glycopyrrolate. Intraoperative analgesia may be accomplished with fentanyl or sufentanil as 
indicated. Postoperatively, the analgesic regimen will be left to the discretion of the physician. 
Patient-controlled analgesia and analgesic adjuncts, such as nonsteroidal anti-inflammatory drugs 
and pregabalin, are allowed. Intraoperative steroids will not be permitted.
On the day of surgery, eligible subjects with 3 or more PONV risk factors will be randomly 
assigned to either Treatment Group A to receive ondansetron placebo IV (administered in not less 
than 30 seconds, preferably over 2 to 5 minutes) immediately before induction of anesthesia 
[Zofran USPI] and prophylaxis with 4 mg TAK-951 SC approximately 30 to 45 minutes before the 
end of surgery (defined as wound closure) or Treatment Group B to receive 4 mg ondansetron IV 
(administered in not less than 30 seconds, preferably over 2 to 5 minutes) immediately before 
induction of anesthesia and TAK-951 saline placebo SC administered approximately 30 to 
45 minutes before the end of surgery.
Study drugs will be dosed sequentially: ondansetron or matching ondansetron placebo prior to 
induction of anesthesia [ie, before surgery], and TAK-951 or matching TAK-951 placebo prior to 
wound closure [ie, during surgery]. After randomization to Treatment Group A or B, subjects must 
demonstrate eligibility based on HR, BP, and cardiovascular stability before administration of 
each dose of study drug; these postrandomization criteria for study drug treatment are in addition 
to exclusion criterion #14 (Section 7.2) which applies to subject eligibility for enrollment and 
randomization. 
For subjects who have been randomized but have not yet received ondansetron or matching 
ondansetron placebo, all subjects must demonstrate average of duplicate measurements of (1) HR 
≥55 and ≤100 bpm, (2) SBP ≥90 mm Hg, and (3) DBP ≥60 mm Hg prior to administration of 
ondansetron or matching ondansetron placebo at induction. Subjects who fail to meet these criteria 
should not receive ondansetron or matching ondansetron placebo and will be discontinued from 
the study. The corresponding decision to hold the dose and withdraw the subject should be 
recorded in the (e)CRF (see Section 7.7). 
Immediately prior to administration of TAK-951 or matching TAK-951 placebo, all subjects must 
demonstrate average of duplicate measurements of (1) HR ≥55 and ≤100 bpm, (2) SBP ≥90 mm 
Hg, and (3) DBP ≥60 mm Hg. If these gating criteria are not met, further assessment of BP and HR 
must be performed as follows to determine eligibility for TAK-951 or matching TAK-951 placebo 
dosing (both HR and BP criteria must be met before proceeding with the second dose of study 
drug): 
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1. If the average SBP is <90 mm Hg or the average DBP is <60 mm Hg, then the average mean 
arterial pressure (MAP) should be measured and evaluated. If the average of duplicate 
measurements of MAP is ≥70 mm Hg, then dosing with TAK-951 or matching TAK-951 
placebo may proceed. If the duplicate average MAP is <70 mm Hg, the anesthesiologist may 
reassess eligibility for dosing. During the next 15 minutes (reassessment period of up to 
15 ±2 minutes), the MAP will be recorded from at least 3 independent BP cuff cycle readouts; 
if the MAP is <70 mm Hg on 2 or more repeat assessments, TAK-951 or matching TAK-951 
placebo should not be administered and the corresponding decision to discontinue dosing 
should be recorded in the (e)CRF. If the MAP is ≥70 mm Hg during the 15-minute 
reassessment period and the MAP is not <70 mm Hg on 2 or more repeat assessments, 
TAK-951 or matching TAK-951 placebo dosing may proceed. A categorical decision tree for 
determining TAK-951 or matching TAK-951 placebo dosing eligibility based on BP is 
provided in Figure 6.a. 
Figure 6.a
BP Criteria for TAK-951 or Matching TAK-951 Placebo Dosing
BP: blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; SBP: systolic blood pressure; 
VS: vital sign.
a Reassessment period up to 15 ±2 minutes for 3 independent BP readings.
b Assessments will be single measurements (NOT duplicate averages) during the 15-minute window.
c If the answer to either question (1 or 2) is “No” then TAK-951/placebo should not be administered.
2. If the average HR is <55 or >100 bpm, the anesthesiologist may reassess within the next 
15 minutes (reassessment period of up to 15 ±2 minutes). Although HR is continuously 
monitored, recorded HR(s) will align with the BP cuff readout (if BP is recorded, the same 
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TAK-951
Study No. TAK-951-2001
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CONFIDENTIAL
timepoint[s] will be used). If the HR is <55 or >100 bpm on 2 or more independent 
assessments during the 15-minute reassessment period, TAK-951 or matching TAK-951 
placebo should not be administered and the corresponding decision to discontinue dosing 
should be recorded in the (e)CRF. If the HR is ≥55 or ≤100 bpm during the 15-minute 
reassessment period and is not <55 or >100 bpm on 2 or more repeat assessments, TAK-951 or 
matching TAK-951 placebo dosing may proceed. A categorical decision tree for determining 
TAK-951 or matching TAK-951 placebo eligibility based on HR is provided in Figure 6.b. 
Figure 6.b
HR Criteria for TAK-951 or Matching TAK-951 Placebo Dosing
BP: blood pressure; HR: heart rate; VS: vital sign.
a Reassessment period up to 15 ±2 minutes for 3 independent HR assessments.
b Assessments will be single measurements (NOT duplicate averages) during the 15-minute window.
c If the answer to either question (1 or 2) is “No” then TAK-951/placebo should not be administered.
If there are signs suggestive of cardiovascular instability during surgery or the subject fails to meet 
the defined vital sign criteria above (as evaluated by the anesthesiologist), TAK-951 or matching 
TAK-951 placebo should not be administered and the corresponding decision to hold the dose and 
withdraw the subject should be recorded in the (e)CRF (see Section 7.7). Subjects who do not 
receive TAK-951 or matching TAK-951 placebo will be unblinded to the investigator; those who 
received placebo at induction of anesthesia as their first dose of study drug will be discontinued 
from the study, and those who received ondansetron will continue to be monitored and assessed to 
study completion per-protocol.
Subjects having 1 or more episodes of vomiting/retching or significant nausea, defined as nausea 
score ≥4 measured on a 0 to 10 verbal response scale (VRS) after surgery, (0 = no nausea at all and 
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10 = the worst nausea imaginable) or upon subject’s request, will receive recommended rescue 
therapy as outlined in Section 7.5 and be considered a treatment failure (see Appendix B). 
Subjects will be monitored for the occurrence of emesis and the occurrence and severity of any 
nausea within the first 24 hours after surgery. Emesis will include vomiting, defined as the forceful, 
discharge of even the smallest amount of stomach contents; or retching, defined as the same 
muscular actions as vomiting but without expulsion of stomach contents. Nausea will be defined as 
the urge to vomit without the presence of expulsive muscular movements. The subject will be 
questioned by the site staff about the severity of nausea using a subject-reported 0 to 10 VRS, 
where 0 represents no nausea and 10 represents the worst nausea imaginable at 1, 2, 6, and 24 
hours after completion of surgery (wound closure). Any spontaneous complaints of nausea by 
subjects will also be noted and assessed for severity. 
Subjects may be discharged 24 hours post surgery after completion of all scheduled procedures. 
There will be a follow-up visit on Day 14±2 for assessment of concomitant medications, AEs and 
blood sample for immunogenicity assessment.
An interim analysis for futility may be conducted after approximately 50 subjects have received 
both doses of double-blind study drug/matching placebo before surgery and during surgery and 
then have either completed all study procedures or withdrawn from the study. The study may be 
stopped if the Bayesian predictive probability calculated based on the interim data meets the 
prespecified stopping rule criteria for futility; otherwise in the absence of safety concerns, the 
study will continue without modification. Futility is nonbinding. Additional descriptive analysis 
for primary and selected secondary and/or exploratory efficacy endpoints may be performed for 
both treatment arms to aid the internal decision-making. Other additional interim analysis of safety 
and/or efficacy may be conducted and would be defined in the SAP.
A schematic of the study design is included as Figure 6.c. A schedule of assessments is listed in 
Appendix A.
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Figure 6.c
Schematic of Study Design
ADA: antidrug antibody; FU: follow-up; IV: intravenous; PACU: postanesthesia care unit; SC: subcutaneous.
a Vital sign criteria must be met according to Figure 6.a and Figure 6.b for eligibility to receive second dose of study 
drug (ie, TAK-951 or matching TAK-951 placebo) during surgery, approximately 30 to 40 minutes before wound 
closure.
6.2
Justification for Study Design, Dose, and Endpoints
A randomized, double-blind, double-dummy, active-controlled study design is considered 
adequate to assess the safety, efficacy, and tolerability of TAK-951 for the prophylaxis of PONV 
in high-risk subjects aged ≥18 years who are undergoing elective surgery under general anesthesia.
The proposed double-dummy design will ensure study blinding while the active-controlled study 
design will ensure that all enrolled subjects receive active medication. 
Ondansetron is approved and widely used to prevent nausea and vomiting that may be caused by 
surgery, cancer chemotherapy, or radiation treatment and as such, is considered an appropriate 
active comparator for use in this study. The dose and route of administration of ondansetron is 
aligned with the label for the prophylaxis of PONV. 
As TAK-951 is currently in the early stages of development, there is no information on efficacy. 
Information on the safety and PK profile of TAK-951 is based on the recently completed 
TAK-951-1001 FIH study in healthy volunteers (see Section 4.1.2 for details). Based on the 
tolerability and exposure/concentration data and population PK modeling, a dose of 4 mg was 
chosen for this study. 
The PK and safety endpoints are standard for this type of study, are used widely, and are 
recognized as reliable, accurate, and relevant. 
Recording of reports of emesis and presence and severity of nausea spontaneously and at 
predetermined intervals after surgery is a standard and appropriate means of assessing the efficacy 
of investigational medicinal products for the prophylaxis of PONV. 
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6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
If during the study any of the following study stopping criteria listed below are met, the study will 
be stopped and the safety data will be reviewed by an external DMC. A recommendation will be 
made to continue, modify, temporarily suspend, and/or terminate the study.

New information or other evaluation regarding the safety or efficacy of the study drug 
indicates a change in the known benefit/risk profile for TAK-951 such that the benefit/risk 
ratio is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) compromises the ability to achieve the 
primary study objectives or compromises subject safety.

Two or more subjects experience a National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 or higher AE considered related to study drug 
by the investigator and/or by the sponsor. Monitoring will occur from TAK-951 administration 
to 24 hours after surgery.

Two or more subjects who, during the operative period, experience a >30% decrease in SBP or 
DBP after TAK-951 administration compared with gated vital sign values immediately before 
TAK-951 dosing (see Section 6.1 for details) or have an absolute HR >120 bpm following 
TAK-951 dosing that are considered related to TAK-951 study drug by the investigator and/or 
by the sponsor. 

One subject experiences an SAE considered to be drug-related by the investigator and/or by 
the sponsor.

One subject experiences an event listed as a Takeda Medically Significant Event (Table 10.a) 
that is considered drug-related by the investigator.

One subject who, during the postoperative period, experiences a >50% change in SBP or DBP 
compared with preoperative vital signs that is considered related to TAK-951 study drug by the 
investigator and/or sponsor. This event will be reported as an SAE to the sponsor within 24 
hours of observation by the investigator. 

One subject who, during the postoperative period, has an absolute HR >120 bpm with 
symptoms (eg, palpitations, light-headedness) that is considered related to TAK-951 study 
drug by the investigator and/or sponsor. This event will be reported as an SAE to the sponsor 
within 24 hours of observation by the investigator. 

Vital signs following TAK-951 or matching TAK-951 placebo administration during the 
operative period should be compared with vital signs obtained in the operating room just 
before TAK-951 or matching TAK-951 placebo dosing. Vital signs after TAK-951 or 
matching TAK-951 placebo administration following the operative period (when patient is in 
PACU and on the floor) should be compared with the preoperative vital signs (before induction 
and before administration of any premedication) obtained the day of surgery.
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
One subject experiences a clinically significant arrhythmia that is considered drug-related by 
the investigator and/or by the sponsor.
One interim analysis, with the objective of potentially stopping the trial for futility, may be 
conducted when approximately 50 subjects have received both doses of double-blind study 
drug/matching placebo before surgery and during surgery and then have either completed all study 
procedures or withdrawn from the study.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement; is unable to ensure 
adequate performance of the study; or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
Subject eligibility is determined according to the following inclusion and exclusion criteria before 
entry into the study:
7.1
Inclusion Criteria
1. Male or female subjects aged ≥18 years at screening. 
2. Subjects undergoing elective surgery under general anesthesia, expected to last for at least 
1 hour from induction of anesthesia to wound closure.
3. Subject is expected to require, or has agreed to stay, at least 1 overnight in the hospital.
4. The subject’s American Society of Anesthesiologist physical status is ASA I-III.
5. Subjects with 3 or more Apfel risk factors: 
a) Female sex.
b) Nonsmoking status (never smoked or stopped smoking ≥12 months ago).
c) History of PONV or motion sickness.
d) Planned use of postoperative opioid analgesics.
6. Subjects of nonchildbearing potential or subjects of childbearing potential willing and 
agreeable to use highly effective contraception or sexual abstinence during the study and up to 
30 days post treatment. See Sections 9.1.10 and 9.1.11 for definitions.
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7.2
Exclusion Criteria
1. Subjects who are expected to remain intubated post anesthesia.
2. Subjects who experience nausea or vomiting within 24 hours before surgery or are diagnosed 
with gastroparesis, cyclic vomiting syndrome, or other condition associated with acute or 
chronic nausea and vomiting.
3. Subjects with a history of allergic reaction to, intolerances of, or contraindications for any of 
the study medications or required anesthetic agents, including any component of the 
formulation of ondansetron or TAK-951.
4. Subjects who have received, or are expected to receive, any excluded drug preoperatively 
within 24 hours before induction, during surgery, or within 24 hours after surgery. See Section 
7.4 for details.
5. Subjects scheduled to receive neuraxial anesthesia (eg, epidural, spinal, or caudal anesthesia), 
regional blocks, or total IV anesthesia, and/or planned to receive different drugs for 
premedication, induction, maintenance, or reversal of anesthesia than those specified in the 
protocol. 
6. Subjects who have an allergy or contraindication to the recommended and available rescue 
therapy for treatment of PONV (see Section 7.5 for list of recommended medications).
7. Subjects expected to require the use of a nasogastric or oral gastric tube after surgery.
8. Female subjects who are pregnant or lactating.
9. Subjects with documented history of alcohol and/or drug abuse within 1 year of study 
medication.
10. Subjects who have any other significant, uncontrolled organic or systemic medical condition 
or social circumstance that, in the investigator’s opinion, make participation in this clinical 
study inappropriate.
11. Subjects found at screening to have a QTcF ≥450 msec or other factors that increase the risk of 
QT prolongation or arrhythmic events. Assessments showing bundle branch block and a 
prolonged QTcF should be discussed with the study monitor and the sponsor for potential 
inclusion.
12. Subjects who have direct family history of premature sudden death or channelopathy, personal 
history of Brugada syndrome (right bundle branch block pattern with ST elevation in leads 
V1-V3), long QT, short QT, arrhythmogenic right ventricular dysplasia, hypertrophic 
cardiomyopathy or catecholaminergic polymorphic ventricular tachycardia (VT).
13. Subjects who have had 3 incidents of vasovagal syncope within the last 5 years. 
14. Subjects with an average HR <55 or >100 bpm or an SBP <90 mm Hg or DBP <60 mm Hg 
during screening or prior to randomization on the day of surgery. 
Note: Vital sign criteria must be met postrandomization, before administration of ondansetron 
or matching ondansetron placebo and as gating criteria before administration of TAK-951 or 
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matching TAK-951 placebo (see Section 6.1 for details). Subjects who exhibit signs 
suggestive of cardiovascular instability (as evaluated by the anesthesiologist) before 
administration of either dose of study drug/matching placebo should not be dosed, and the 
corresponding decision should be recorded. 
15. Subjects with a clinically significant ECG abnormality indicative of acute cardiac instability as 
determined by the investigator at screening, including more than first-degree atrioventricular 
block, nonsustained or sustained VT, or ECG changes consistent with acute myocardial 
ischemia or infarction. 
16. Subjects with a history of acute myocardial ischemia within the last 12 months.
17. Subjects receiving beta blockers chronically or between screening and surgery that cannot be 
safely withheld on the day of surgery in the investigator’s judgment. Subjects receiving certain 
other cardiovascular medications, such as vasodilators for hypertension, chronically or 
between screening and surgery that in the investigator’s judgment cannot be adequately 
managed in the perioperative setting considering the potential vasodilator effects of TAK-951 
and anesthesia standard of care. The investigators must consult with the medical monitor 
regarding eligibility of subjects who are receiving beta blockers, vasodilators, and other 
classes of medications that act on HR or BP. 
18. Subjects with an alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >2 times the upper limit of normal ULN or total bilirubin >1.5 times the ULN.
19. Subjects with known liver disease or positive for hepatitis B or C. For hepatitis B/C, 1 of the 
following is present at screening:

Chronic hepatitis B virus infection: positive for hepatitis B surface antigen (HBsAg).

Chronic hepatitis C virus (HCV) infection: positive for HCV antibody that is confirmed 
with a positive HCV RNA viral load test (those treated and cured for HCV infection are 
allowed).
20. Subjects who have participated in an interventional clinical study or been exposed to any 
experimental drug within 30 days before enrollment of this study.
21. Subjects who are an immediate family member, study site employee, or 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.
7.3
Potential Drug Interactions
7.3.1
Synergistic Effect When Combined With Propranolol and Sevoflurane
TAK-951 administration to sevoflurane-anesthetized dogs resulted in decreases in systemic BP 
(including SBP and DBP) immediately following dosing, which were maximal within 10 minutes 
postdose and partially recovered, but remained decreased relative to predose levels up to 1 hour 
postdose, with a similar magnitude of change at all doses. There was a minimal increase in HR 
noted within 15 minutes post dose that remained through the anesthesia monitoring. Following 
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recovery from the anesthesia and return to their home cage, there was a decrease in systemic BP 
(including SBP and DBP) with marked increases in HR noted for the remainder of the monitoring. 
The magnitude of the BP and HR changes, measured in intervals of 4 hours, in the conscious 
animals were generally dose-related. 
The effects of TAK-951 in combination with the beta blocker propranolol on the CV system were 
investigated in telemeterized conscious dogs in a non–GLP-compliant exploratory study. 
Propranolol partially suppressed the TAK-951–mediated HR effects, limiting the magnitude and 
duration of the HR increase. Administration of either TAK-951 or propranolol decreased BP. 
Combination treatment resulted in a greater BP decrease relative to either treatment alone.
7.4
Excluded Medications
Excluded medications include:

Antiemetics, other than the study drugs, are prohibited within 24 hours before and up to 
24 hours after surgery except for postoperative rescue therapy. Any drug given in the 24-hour 
postoperative period that would be expected, by virtue of its pharmacology, to exert a 
clinically meaningful antiemetic effect, even if not administered for that purpose (eg, 
metoclopramide administered for postoperative ileus), are not permitted.

Nitrous oxide will not be permitted during surgery. 

Total IV anesthesia or propofol infusions for maintenance of anesthesia will not be permitted 
during surgery. 

Intraoperative steroids will not be permitted. 
7.5
Rescue Therapy
Subjects will be assigned 1:1 on a double-blind basis to ondansetron, an approved medication for 
PONV prophylaxis, or TAK-951, an investigational treatment. Recommended rescue therapy 
should be given in accordance with product package inserts, the assessments in this protocol, 
standard of care for rescue treatment for PONV, and the “Fourth Consensus Guidelines for the 
Management of Postoperative Nausea and Vomiting” [14]. Rescue treatment should be based on 
timing of rescue relative to investigational product dosing, local standard of care, and drug 
availability. Specific recommendations for rescue therapy in this study are as follows:
1. If rescue therapy is required within 6 hours of administration of study drug (TAK-951 or 
time-matched placebo), promethazine 6.25 mg IV or amisulpride 10 mg IV are recommended.
2. If rescue therapy is required 6 or more hours after administration of study drug (TAK-951 or 
time-matched placebo), ondansetron 4 mg IV is recommended. If further rescue therapy is 
required, promethazine 6.25 mg IV or amisulpride 10 mg IV are recommended.
Other rescue treatment alternatives are not recommended. In choosing rescue treatment 
recommendations for PONV at any time after study drug, the potential for PK and 
pharmacodynamic (PD) interactions (including those with a risk for potential QTc prolongation) 
should be considered, with reference to the ondansetron package insert, promethazine package 
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insert, BARHEMSYS (amisulpride) package insert, and TAK-951 IB, particularly if timing of 
rescue is within 6 hours of administration of study drug (TAK-951 or matching placebo).
7.6
Diet, Fluid, Activity Control
Subjects should remain in a semirecumbent position, lateral semirecumbent position (if actively 
vomiting to avoid the risk of aspiration), or seated (if tolerated) and monitored closely for at least 3 
hours after administration of study drug due to the risk of postural hypotension. Subjects should 
avoid standing or walking unaccompanied during this interval of time. 
There are no specific restrictions on diet and fluids associated with this study. Sites should follow 
their standard guidelines or Enhanced Recovery After Surgery protocol. 
7.7
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 (e)CRF using the following categories. For screen failure subjects, refer 
to Section 9.1.14.
1. Pretreatment event (PTE) or AE. 

The subject has experienced a PTE or AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health, or the subject is 
unwilling to continue because of the PTE or AE.

Subjects with liver test abnormalities should be evaluated to determine whether study drug 
should be continued, interrupted, or discontinued (Appendix G). 
2. Significant protocol deviation. The discovery after randomization 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. Ineligibility for first dose of study drug. The subject was ineligible to receive the first dose of 
study drug (ie, ondansetron or matching ondansetron placebo) based upon vital sign criteria 
outlined in Section 6.1.
4. Ineligibility for second dose of study drug, after receiving placebo as first dose. The subject 
received placebo as the first study drug (ie, randomized to ondansetron placebo) but was not 
eligible to receive the second dose of study drug (ie, TAK-951) based upon vital sign criteria 
outlined in Section 6.1.
5. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
6. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
(e)CRF.
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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE and/or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
7. Study termination by the sponsor.
8. Study termination by the IRB or regulatory agency.
9. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately as 
described in Section 9.1.11.
10. 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. 
7.8
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.7. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit. 
The following subjects will be replaced: 

Discontinued subjects who were ineligible to receive the first dose of study drug 
(ie, ondansetron or matching ondansetron placebo) based upon vital sign criteria outlined in 
Section 6.1.

Discontinued subjects who were ineligible to receive the second dose of study drug (ie, 
TAK-951 or matching TAK-951 placebo) based upon vital sign criteria outlined in 
Section 6.1. 

Subjects may be replaced as appropriate based on significant protocol deviations.
Discontinued or withdrawn subjects for any other reason will not be replaced.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug and Materials
8.1.1
Study Drugs
In this protocol, the term study drug refers to all or any of the drugs defined below. TAK-951 SC 
injection and ondansetron will be provided to the investigator by the sponsor in an open-label 
manner. These medications will be prepared and blinded by the unblinded site pharmacist before 
administration. 
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Details regarding the dosage form description and strengths or composition for the 
extemporaneous preparation of the active drug and placebo can be found in the pharmacy manual 
or in the referenced compounding manual when applicable. Study drug will be packaged to 
support enrollment and replacement of subjects as required.
8.1.1.1
TAK-951
TAK-951 will be supplied 
 in an 
appropriately labeled carton with a single panel label that will contain, but not be limited to, the 
sponsor’s name and address, protocol number, packaging job/lot number, name and strength of the 
product, caution statement, and storage conditions.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Ondansetron
Ondansetron will be supplied as 4 mg/2 mL (2 mg/mL), from a commercial source, and provided 
in labeled glass vials packaged in an appropriately labeled carton. Additional reference 
information and administration instructions can be found in the pharmacy manual.
8.1.1.3
Placebo
Placebo will be 0.9% normal saline supplied by the study sites. 
8.1.2
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers in accordance with local regulatory
requirements.
8.1.3
Clinical Study Drug Inventory and Storage
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained.
TAK-951 must be stored at -25°C to -15°C with protection from light.
Ondansetron must be stored at 20° to 25°C (68°F to 77°F) per United States Pharmacopeia at a 
controlled room temperature with protection from light.
The temperature excursion information can be found in the pharmacy manual or in the referenced 
compounding manual when applicable. Receipt and dispensing of study drug must be recorded by 
authorized personnel at the study site.
8.1.4
Dose and Regimen
Table 8.a describes the dose that will be provided to each treatment group.
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Table 8.a
Dose and Regimen
Treatment Group
Dose
Treatment Description
Prophylaxis
A
Ondansetron placebo IV
Immediately before induction administered 
in not less than 30 seconds, preferably over 2 
to 5 minutes
4 mg TAK-951 SC
~30 to 45 minutes before the end of surgery a
B
4 mg ondansetron IV
Immediately before induction administered 
in not less than 30 seconds, preferably over 2 
to 5 minutes
TAK-951 placebo SC
~30 to 45 minutes before the end of surgery a
IV: intravenous; SC: subcutaneous.
a The end of surgery is defined as wound closure.
8.1.5
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 in the (e)CRF to 
capture this important safety information consistently in the database. Cases of overdose without 
manifested signs or symptoms are not considered AEs. AEs associated with an overdose will be 
documented on AE CRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
The investigator or the investigator’s designee will access the interactive response technology 
(IRT) at screening to obtain the subject study number. The investigator or the investigator’s 
designee will also utilize the IRT to randomize the subject into the study. During this contact, the 
investigator or designee will provide the necessary subject-identifying information, including the 
subject number assigned at screening. Subjects will be assigned in a 1:1 ratio to receive 
prophylaxis with 4 mg TAK-951 or 4 mg ondansetron according to the randomization schedule. 
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 or the sponsor’s designee will generate the randomization 
schedule and will provide it to the IRT vendor before the start of the 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 the 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, changing a medication ID 
number in order to avoid identification of subjects by the laboratory site personnel).
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. The 
study will be conducted sponsor-open. Sponsor discussions with investigators and within the study 
team will be conducted in a blinded manner (ie, no unblinded information will be communicated to 
blinded investigators, site staff, or blinded study monitoring personnel).
8.5
Unblinding Procedure
For subjects who receive both doses of study drug (ie, ondansetron or matching ondansetron 
placebo, and TAK-951 or matching TAK-951 placebo):

The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. All study assessments and 
causality assessment should be performed, if possible, 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.

If any site personnel are unblinded, the subject must be withdrawn from the study.
For subjects who receive the first dose of study drug (ie, ondansetron or matching ondansetron 
placebo), but are ineligible to receive the second dose of study drug (ie, TAK-951 or matching 
TAK-951 placebo) due to failure to meet the vital sign criteria described in Section 6.1:

The blind shall be broken by the investigator. If the subject received ondansetron placebo as 
the first dose of study drug, they should be discontinued from the study. If the subject received 
ondansetron as the first dose of study drug, they should remain in the study for ongoing 
monitoring and assessments to study completion per-protocol. A schematic of the unblinding 
procedure for subjects who do not receive TAK-951 or matching TAK-951 placebo is 
presented in Figure 8.a.
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Figure 8.a
Unblinding Procedure for Subjects Ineligible to Receive TAK-951 or 
Matching TAK-951 Placebo
a Vital sign criteria for eligibility to receive TAK-951 or matching TAK-951 placebo detailed in Section 6.1.
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, including 
subjects who are unblinded due to study drug ineligibility (ie, failure to meet the vital sign criteria 
outlined in Section 6.1). 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 in the (e)CRF.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator or designee must ensure that the study drug is used in accordance with the 
protocol and is dispensed only to subjects enrolled in the study. To document appropriate use of 
study drug (TAK-951 or ondansetron), the investigator or designee must maintain records of all 
study drug deliveries to the site, site inventory, dispensation and use by each subject, destruction of 
drug supply at the site, and/or study drug returned to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must promptly verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct and that the study drug is in good condition. If there are any discrepancies between the 
packing list versus the actual product received, the sponsor (or representative) must be contacted to 
resolve the issue as outlined in the pharmacy manual. The packing list should be filed in the 
investigator’s essential document file.
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The investigator or designee must maintain 100% accountability for all study drugs during his or 
her entire participation in the study. Proper drug accountability includes, but is not limited to, the 
following:

Frequent verification that actual inventory matches documented inventory.

Verification that the log is completed for the drug lot (or medication ID number) used to 
prepare each dose.

Verification that all containers used are documented accurately on the log.

Verification that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all study drugs (TAK-951 and 
ondansetron) 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; date and amount dispensed including initials, 
seal, or signature of the person dispensing the drug; and the date and amount returned to the site by 
the subject, including the initials, seal, or signature of the person receiving the sponsor-supplied 
drug. The log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
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 and signed before the subject enters into the study and before 
any protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information, medical history, and medication history will be obtained at the 
screening visit and before surgery. 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 before signing of informed consent. Ongoing conditions are considered 
concurrent medical conditions (see Section 9.1.8). Medication history information to be obtained 
includes any medication relevant to eligibility criteria before signing of informed consent.
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The Simplified Apfel Risk Score includes the 4 most relevant risk factors for PONV (female sex, 
history of PONV and/or of motion sickness, nonsmoking status, and postoperative use of opioids) 
that is currently used in clinical practice and research as a simple tool to identify subjects at higher 
risk of PONV.
9.1.3
Physical Examination Procedure
A baseline physical examination conducted at the screening visit will consist of the following body 
systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; 
(5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; 
(9) nervous system; and (10) lymph nodes. Any subsequent physical examinations should assess 
clinically significant changes from the assessment before the screening examination.
9.1.4
Height, Weight, and BMI
Height and weight will be measured wearing indoor clothing and with shoes off and will be 
measured at the screening visit only. Body mass index (BMI) is calculated using metric units with 
the formula provided below. Height is recorded in centimeters without decimal places. Weight is 
collected in kilograms (kg) with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height = 176 cm 
(1.76 meters) and weight = 79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2
The values should be reported to 1 decimal place by rounding. Thus, in the above example, BMI 
would be reported as 25.6 kg/m2. 
9.1.5
Vital Sign Procedure 
Vital signs (HR, BP, respiratory rate [RR]) will be collected in duplicate and averaged at all time 
points. Vital signs will be collected at screening, before dosing with ondansetron or matching 
ondansetron placebo (ie, before surgery), immediately before dosing with TAK-951 or matching 
TAK-951 placebo (ie, during surgery), and at the end of surgery (defined as wound closure, see 
Figure 6.c) and recorded in the (e)CRF. During surgery, vital signs will be monitored continuously 
for safety purposes. HR and BP will be collected in duplicate for all vital sign measurements 
within a 2-minute interval and the results averaged for higher accuracy. Vital signs can be repeated 
within 10 minutes, if at screening or before surgery, the physician believes that these are 
artificially high due to subject’s anxiety. Body temperature will also be taken before surgery and 
approximately 8 and 24 hours post surgery or TAK-951 dosing.
Immediately prior to TAK-951 or matching TAK-951 placebo dosing, criteria for BP and HR must 
be met and cardiovascular stability demonstrated (see Section 6.1, Figure 6.a, and Figure 6.b). If 
there are signs suggestive of cardiovascular instability during surgery (as evaluated by the 
anesthesiologist), TAK-951 or matching TAK-951 placebo should not be administered and the 
corresponding decision should be recorded in the (e)CRF. 
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During the immediate postsurgical period, vital signs will be monitored upon admittance to the
PACU and collected every 15 minutes until 1 hour post surgery, then every 30 minutes until 
4 hours postsurgery, then every hour until 8 hours postsurgery, then every 6 hours until 24 hours 
postsurgery, and again at discharge.
When vital signs are scheduled at the same time as blood draws, the vital signs will be taken just 
before blood draws.
9.1.6
Efficacy/Patient Reported Outcomes Measurement
9.1.6.1
Postsurgery Assessment of Nausea
Postoperative nausea (described as the desire to vomit without the presence of expulsive muscular 
movements) will be scored using a self-reported, 11-point numerical VRS where 0 represents “no 
nausea” and 10 represents the “worst nausea possible.” Significant nausea is defined as a VRS ≥4.
The presence and severity of subject-reported nausea anytime during the 24-hour follow-up period 
will be recorded by the site staff in a paper form (see Appendix B) and the (e)CRF. Nausea will 
also be assessed by direct questioning by the site staff at 30 minutes and 1, 2, 6, and 24 hours post 
surgery (wound closure) and results will be recorded similarly. 
9.1.6.2
Emetic Events
Emesis is defined as vomiting (the forceful discharge of even the smallest amount of stomach 
contents) or retching (the same muscular movements as vomiting but without expulsion of 
stomach contents). The occurrence and timing of emetic events will be monitored and documented 
by the subject or site staff in a paper form (see Appendix C) and the (e)CRF. 
9.1.7
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the (e)CRF.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the screening examination according to the judgment of the 
investigator. The condition (ie, diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and required safety monitoring will be given in the study procedures manual.
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Clinical laboratory evaluations (hematology and serum chemistry) do not need to be repeated on 
the day of surgery if the screening assessments were performed within 2 weeks, did not show any 
clinically relevant abnormalities, and were discussed with the medical monitor. If repeated, 
baseline clinical labs performed on the day of surgery do not need to be reviewed before dosing.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Red blood cells
White blood cells
Hemoglobin
Hematocrit
Platelets
AST
ALT
Albumin
Alkaline phosphatase
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
GGT
Glucose 
Potassium
Sodium
Other:
Serum
Urine
Hepatitis panel, including HBsAg and anti-HCV
Immunogenicity
Female subjects only:
hCG (for pregnancy)
Female subjects only:
Beta hCG (for pregnancy) in female subjects of 
childbearing potential
FSH in female subjects for whom menopause is 
suspected
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; GGT: 
γ-glutamyl transferase; HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV: hepatitis C 
virus.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis for hCG. The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. A central laboratory will perform the ADA 
assessments. 
For subjects with treatment-emergent ALT elevations ≥3 times the ULN, see Appendix G for 
additional monitoring, evaluation, and follow-up recommendations.
The investigator (or designee) is responsible for transcribing or attaching laboratory results to the 
(e)CRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used.
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9.1.10
Contraception and Pregnancy Avoidance Procedure
9.1.10.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives or 30 
days after the last dose of study drug, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with or 
without spermicidal cream or jelly). In addition, they must be advised not to donate sperm during 
this period. Women of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception below.
9.1.10.2
Female Subjects and Their Male Partners 
From signing of informed consent, throughout the duration of the study, and for 5 half-lives or 30 
days after the last dose of study drug, female subjects of childbearing potential* who are sexually 
active with a nonsterilized male partner** must use at least 1 highly effective method of 
contraception (Section 9.1.10.3). In addition, they must be advised not to donate ova during this 
period.
9.1.10.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (WOCBP), ie, 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. A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range (FSH >40 IU/mL) may be used to confirm a 
postmenopausal state in younger women (eg, those aged <45 years) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized men should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly)”. In this study, where medications and devices containing hormones are included, 
the only acceptable methods of contraception are as follows: 

Nonhormonal methods: 
–
Intrauterine device. 
–
Bilateral tubal ligation. 
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–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success). 
–
True sexual abstinence, but only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month before the first dose until 5 
half-lives or 30 days after last dose. 

Hormonal methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, or concomitant medications, which may reduce the 
efficacy of the contraception method.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug OR 
combined with a barrier method (male condom, female condom, or diaphragm) if for 
shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation initiated 
at least 3 months prior to the first dose of study drug OR combined with a barrier method 
(male condom, female condom, or diaphragm) if shorter until she has been on 
contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. Effective methods of contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams, PLUS male condom).

Progestogen-only hormonal contraception in which inhibition of ovulation is not the 
primary mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.
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
Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
4. Subjects will be provided with information on effective/highly effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy and 
donation of ova or sperm donation during the course of the study.
5. During the course of the study, all subjects (male and female) will receive continued guidance 
with respect to the avoidance of pregnancy or sperm donation as part of the study procedures. 
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
6. In addition to a negative serum human chorionic gonadotropin (hCG) pregnancy test at 
screening, female subjects of childbearing potential must also have confirmed menses in the 
month before first dosing (no delayed menses) and a negative urine hCG pregnancy test on the 
day of surgery before receiving any dose of study medication.
9.1.10.4
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study

Reasons for use of barrier methods (ie, condom) in men with pregnant partners.

Important in all studies with IMPs/comparators/background medications that are known for 
teratogenicity/fetotoxicity or in the absence of reproductive toxicity results.
From signing of informed consent and throughout the duration of the study and for 5 half-lives or 
30 days after the last dose, WOCBP (ie, nonsterilized, premenopausal female subjects) who are 
sexually active must use acceptable methods of contraception. Also, from signing of informed 
consent, throughout the duration of the study, and for 5 half-lives or 30 days after the last dose, 
nonsterilized male subjects who are sexually active with a female partner of childbearing potential 
must use contraception. Such subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy during the course of 
the study. Serum and urine hCG pregnancy tests will be performed at screening and before surgery, 
respectively, and subjects will receive continued guidance with respect to avoiding pregnancy as 
part of the study procedures (Appendix A).
In addition to a negative serum hCG pregnancy test at screening, subjects also must have a 
negative urine hCG pregnancy test on the day of the dose of study drug (predose) before receiving 
any dose of study drug.
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In addition, male subjects must be advised not to donate sperm from signing of informed consent 
to 5 half-lives after the last dose of study drug.
9.1.11
Pregnancy
If pregnancy occurs following study drug administration, defined as within 30 days of the last dose 
of active study drug, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator) will be followed up to final outcome, using the pregnancy form. 
Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
9.1.12
ECG and Telemetry Procedure 
ECGs will be monitored continuously by telemetry during surgery and for the first 24 hours 
postsurgery. A standard 12-lead ECG will be performed at screening, on Day 1 before surgery, on 
admittance to the PACU (approximately 1 hour post dose), and before hospital discharge. In case 
of symptoms (eg, palpitations or dizziness) or if abnormalities are identified on telemetry, a 
12-lead ECG will be performed. 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. ECG parameters will be entered into 
the database for all subjects. All tracings will be available as a source document for review and 
verification by the sponsor. ECGs for all SAEs will be submitted to the sponsor for review. 
The time that the ECG was performed will be recorded. The following parameters will be recorded 
on the (e)CRF from the subject’s ECG trace: HR, RR interval, PR interval, QT interval, and QRS 
interval, and QTcF.
9.1.13
PK, DNA measurements, and Immunogenicity Sample Collection and Analysis
9.1.13.1
Collection of Blood/Plasma/Serum
Blood sample for plasma for determination of TAK-951 concentration will be collected from all 
subjects at time windows specified in Table 9.c. Plasma samples may be analyzed for ondansetron 
concentration, and the results may be reported separately. The samples will be analyzed for plasma 
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concentration of TAK-951 and ondansetron (if performed) by validated methods. Table 9.b
summarizes sampling for PK, DNA measurements, and immunogenicity assessments. Further 
details of the collection and procedures will be given in the study procedures manual.
Table 9.b
Sample Collection for PK, DNA Measurements, and Immunogenicity 
Assessments
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of 
Intended Use
Sample Collection
Plasma sample for TAK-951 PK
Plasma
N/A
PK measurements
Mandatory
Buccal epithelial cells sample for 
DNA 
Buccal swabs
DNA
DNA 
measurements
Optional
Serum sample for immunogenicity
Serum
N/A
Immunogenicity 
assessments
Mandatory
N/A: not applicable; PK: pharmacokinetic. 
It is important that the date and time of administration of the study drug dose before collection of 
the PK sample be recorded accurately in the source documents and the (e)CRF. Similarly, it is 
important that the date and time that each blood sample is drawn is accurately recorded in the 
(e)CRF.
The sparse sampling time windows for blood draws for the analysis of plasma concentrations of 
TAK-951 are shown in Table 9.c.
Table 9.c
PK Sampling Time Windows
PK Sampling Time Windows After SC Dose for Treatment Groups A and B
Window 1
Window 2
Window 3
Window 4 a
Window 5
PK sampling
1-3 h
4-6 h
7-9 h
10-18 h
22-26 h
PK: pharmacokinetic; SC: subcutaneous.
a PK sample at 10-18 h should be as close to 14 h as feasible.
Blood samples 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 (e)CRF. Plasma samples may be used for future metabolite identification and/or 
further evaluation of the bioanalytical methods. These data will be used for internal exploratory 
purposes and will not be included in the clinical study report.
9.1.13.2
Immunogenicity
Protein products have the potential to induce anti-drug immune response which may affect the 
safety and efficacy of TAK-951. Detection and analysis of ADA formation is a helpful tool in 
understanding drug immunogenicity, efficacy, and safety. To understand drug immunogenicity, 
serum samples will be collected before surgery (the baseline sample), at discharge/early 
termination, and at the follow-up visit.
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, an ADA assay may be 
influenced by several factors, including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. Therefore, the incidences of ADA 
formation cannot be directly compared with the other products. ADA samples will be taken in all 
parts of the study across all cohorts. 
9.1.13.3
DNA Measurements
DNA sampling is optional in this study and will only be performed for subjects who provide 
consent to participate in this assessment.
This information may be used to develop a better 
understanding of the safety and efficacy of TAK-951 and other study drugs, to increase 
understanding of the disease/condition being studied, and for improving the efficiency, design, and 
study methods of future research studies. 
DNA research is an evolving science and further assessments may be performed based on newly 
available data. 
Subjects who consent and provide a buccal swab for DNA analysis can withdraw their consent at 
any time and request disposal of a stored sample. Any remaining sample that can be identified as 
coming from the subject will be destroyed. The investigator and sponsor may continue to use and 
distribute any information and test results gathered before the request to withdraw. 
Detailed instructions for collection, storing, handling, and shipping samples will be provided in the 
laboratory manual. 
9.1.13.4
Bioanalytical Methods
The validated bioanalytical method for TAK-951 will be used for the analysis. 
9.1.14
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is withdrawn at the screening visit, the investigator should complete the (e)CRF. The 
IRT should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the (e)CRF using the following categories:
!
PTE/AE.
!
Did not meet inclusion criteria or did meet exclusion criteria. 
!
Significant protocol deviation.
!
Lost to follow-up.
!
Voluntary withdrawal <specify reason>.
!
Study termination. 
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
Other <specify reason>.
Subject identification numbers assigned to subjects who fail screening should not be reused.
9.1.15
Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for enrollment into the study and randomization into the treatment phase.
If the subject is found to be not eligible for randomization to treatment, the investigator should 
record the primary reason for failure on the applicable (e)CRF.
9.2
Monitoring Subject Treatment Compliance
Study site personnel will administer study drug and record in the (e)CRF.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days before surgery. Subjects will be screened in accordance 
with predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.14 for 
procedures for documenting screening failures.
Procedures to be completed at screening include:

Informed consent.

Inclusion/exclusion criteria.

Demographics, medical history, and medication history.

Concomitant medications/therapies.

Simplified Apfel Risk Score.

Physical examination.

Height, weight, BMI, and vital signs (BP, HR, and RR).

Serum pregnancy test (hCG).

FSH, if applicable.

HBsAg and HCV.

Screening clinical laboratory tests.

12-lead ECG.

PTE/AE assessment.
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9.3.2
Day 1
9.3.2.1
Before Surgery
Procedures to be completed before surgery include:

Inclusion/exclusion criteria.

Demographics, medical history, and medication history.

Concomitant medications/therapies. 

Vital signs (BP, HR, and RR).

Body temperature.

Urine pregnancy test (hCG).

Clinical laboratory evaluations.

12-lead ECG.

Randomization to treatment.

AE assessment.

Sampling for immunogenicity.

Sampling for DNA.

Administration of IV study drug or placebo immediately before induction of anesthesia (see 
Section 6.1 for eligibility based on vital sign criteria).
9.3.2.2
During Surgery
Procedures to be completed during surgery include:

Vital signs (BP, HR, and RR).

Concomitant medications/therapies.

Telemetry.

Administration of SC study drug or placebo (see Section 6.1 for eligibility based on vital sign 
criteria).

Assessment of anesthesia and surgical procedure time.

AE assessment.

Plasma sample for TAK-951 PK. The PK sample for the first window (1 to 3 hours after SC 
administration of study drug; see Table 9.c), may be during surgery or in the postsurgery 
observational period (Section 9.3.2.3). 
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9.3.2.3
Postsurgery Observational Period
Procedures to be completed during the postsurgery observational period on Day 1 include:

Vital signs (BP, HR, and RR)

Body temperature (at approximately 8 hours post surgery). 

Concomitant medications/therapies.

12-lead ECG.

Telemetry.

Assessment of nausea.

Assessment of emetic events.

AE assessment.

Plasma samples for TAK-951 PK (see Table 9.c).
9.3.3
Hospital Discharge/Early Termination
Procedures to be completed at hospital discharge/early termination include:

Vital signs (BP, HR, and RR).

Body temperature (at approximately 24 hours post surgery). 

Concomitant medications/therapies.

Clinical laboratory evaluations.

12-lead ECG.

Assessment of nausea.

Assessment of emetic events (up to 24 hours ± 30 minutes post surgery).

AE assessment.

Plasma samples for TAK-951 PK (see Table 9.c and Appendix A).

Serum sample for immunogenicity.
9.3.4
Follow-up Visit 
There will be 1 follow-up visit after hospital discharge, during which the following procedures will 
be performed and documented:

Concomitant medications/therapies.

AE assessment.

Serum sample for immunogenicity.
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For all subjects who received study drug, the investigator must complete the End of Study (e)CRF 
page.
9.3.5
Poststudy 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.
9.4
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.13. 
Details are provided in the study lab manual.
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but before administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
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
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test 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 a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy), 
any occurrence of an episode should only be captured as a PTE/AE if the condition becomes 
more frequent, serious, or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (eg “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).
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
If the subject experiences a worsening or complication of an AE after any change in study drug, 
the worsening or complication should be recorded as a new AE. Investigators should ensure 
that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in intensity of AEs/serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered PTEs or AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as a PTE or an AE. Complications resulting from any planned 
surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs but instead will be documented on the appropriate form (Dosing Injection or 
Dosing Intravenous). Any manifested side effects will be considered PTEs or AEs and will be 
recorded on the AE page of the (e)CRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life-threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
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5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsades de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
COVID-19–related disease
Neuroleptic malignant syndrome/malignant hyperthermia
COVID-19 pneumonia
Spontaneous abortion/stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the aforementioned serious criteria are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
AEs of Special Interest
AEs of special interest for TAK-951 include injection site reactions, hypotension, and tachycardia.
These AEs will be monitored by the investigator and sponsor.
10.1.6
Intensity of PTEs and AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to NCI CTCAE v5.0. AEs not listed by the NCI CTCAE will be graded as 
displayed in Table 10.b.
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Table 10.b
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.
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.
ADL: activities of daily living; AE: adverse event.
10.1.7
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments.
10.1.8
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.9
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
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10.1.12
Action Concerning Study Drug 

Drug Withdrawn – a study drug is stopped due to the particular AE.

Dose Not Changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE).

Dose Reduced – the dose was reduced due to the particular AE.

Dose Increased – the dose was increased due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving.”

Not Recovered/Not Resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
Recovered/Not Resolved.”

Resolved With Sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug or until 
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screen failure. For subjects who discontinue prior to study drug administration, PTEs are collected 
until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug on 
the day of surgery. Routine collection of AEs will continue until the follow-up visit. 
10.2.1.2
PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug or not, 
must be monitored until the symptoms subside and any clinically relevant changes in laboratory 
values have returned to baseline or until there is a satisfactory explanation for the changes 
observed. All PTEs and AEs will be documented in the PTE/AE page of the (e)CRF, whether or 
not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:
1. Event term.
2. Start, stop date, and time. 
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
After discharge and before the 14-day follow-up visit all the patients will be instructed to contact 
the site immediately in case of an AEs. The site will collect all the follow-up information for 
proper medical evaluation by the investigator.
10.2.1.3
AEs of Special Interest 
AEs of special interest for TAK-951 include injection site reactions, hypotension, and tachycardia.
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If an AE of special interest that occurs during the treatment period or the follow-up period is 
considered to be clinically significant based on the criteria below, it should be recorded on the
SAE form. The form should be completed and reported to the pharmacovigilance department
within 24 hours.
The investigator should submit the original copy of the SAE form to the sponsor.
AEs of special interest criteria include: 

Laboratory value threshold, if applicable.

Premature termination for the AE of special interest, if applicable.

Any other specific criteria.
AEs of special interest should be recorded as AEs in the (e)CRF. 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:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s)

Causality assessment.
The SAE form should be transmitted within 24 hours 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.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3
Reporting of Abnormal Liver Function Tests 
For any subject with ALT ≥3 times the ULN AND total bilirubin >2 times the ULN OR
international normalized ratio (INR) >1.5 times the ULN for which an alternative etiology has not 
been found, report the event as an SAE, contact the Medical Monitor and Takeda Trial Clinician 
within 24 hours, and follow the additional monitoring, evaluation, and follow-up 
recommendations in Appendix G.
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10.2.4
Management of Specific AEs
10.2.4.1
Hypotension
If a subject develops symptoms suggestive of hypotension or postural hypotension, BP should be 
assessed for evidence of hypotension, which should be managed as per local guidelines, and the 
medical monitor should be contacted.
10.2.4.2
Injection Site Reactions
If a subject develops a CTCAE Grade 3 (ulceration or necrosis; severe tissue damage, operative
intervention need) or 4 (life-threatening consequences; urgent intervention indicated) event, 
administration of TAK-951 should be discontinued, immediate treatment provided, and the 
medical monitor contacted.
10.2.4.3
Hypersensitivity
If anaphylaxis or other serious allergic reactions occur, study drug administration should be 
discontinued immediately and appropriate management initiated (eg, epinephrine, antihistamines, 
and further immediate care as necessary).
10.2.4.4
Sinus Tachycardia
CTCAE Grade 2 sinus tachycardia (ie, symptomatic; nonurgent medical intervention indicated) 
with HR ≥120 bpm. Evaluate ECG for abnormalities, manage as per local guidelines, and call the 
medical monitor immediately. 
10.2.4.5
Potential Drug Interaction
Based on the available nonclinical dog CV pharmacology study of concomitant dosing of 
TAK-951 and propranolol in dogs, a potential risk of synergistic effect on BP when TAK-951 was 
combined with propranolol has been identified. Caution should be taken if TAK-951 is given with 
any antihypertensive medication, specifically beta blockers or vasodilating agents. If beta blockers 
are deemed necessary in an acute care setting as part of standard of care, use of a short-acting, 
selective beta blocker should be considered. Standard anesthesia protocol should be followed for 
management of HR and BP changes, and treatment should be based upon underlying etiology.
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.
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10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable. 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 in accordance with 
local regulations.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
External DMC
An external independent DMC will conduct ongoing reviews of safety data and the results from 
interim analysis for futility if performed. The DMC will make recommendations to the study team 
as described in the DMC charter. 
Details of the DMC, including meeting frequency, approach to maintaining the study blind 
through appropriate firewalls, will be captured in the DMC charter before 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, PTEs, medical history, and concurrent medical conditions will be coded using the MedDRA. 
Drugs will be coded using the World Health Organization Drug Dictionary.
12.1
(e)CRFs
Completed (e)CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to (e)CRFs. Additionally, the 
contract research organization (CRO) will make available (e)CRF Completion Guidelines that will 
provide clear details on how to complete the forms. These forms are used to transmit the 
information collected in the performance of this study to the sponsor and regulatory authorities. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
The principal investigator must review the (e)CRFs for completeness and accuracy and must 
e-sign the appropriate (e)CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the (e)CRFs.
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(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the (e)CRFs. The 
completed (e)CRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of (e)CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
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.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of subjects’ 
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 before unblinding of subjects’ 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 to treatment and 
received both doses of double-blind study drug (ie, ondansetron or matching ondansetron placebo, 
and TAK-951 or matching TAK-951 placebo) before surgery and during surgery. Subjects will be 
analyzed according to their randomized treatment, regardless of whether they receive an 
investigational product that is different from that to which they were randomized.
The Per-protocol Analysis Set (PPAS) will include all subjects who are in the FAS and do not 
violate the terms of the protocol in a way that would impact the study output significantly. All 
decisions to exclude subjects for the per-protocol population will be made before the unblinding of 
the study. Analyses using the PPAS will be provided as a sensitivity analysis.
The Safety Analysis Set will include all subjects who were randomized to treatment and received 
both doses of double-blind study drug (ie, ondansetron or matching ondansetron placebo, and 
TAK-951 or matching TAK-951 placebo) before surgery and during surgery. In safety summaries, 
subjects will be analyzed according to the treatment they actually received. 
The PK set will consist of all subjects who receive study drug and have at least 1 evaluable PK 
sample.
The immunogenicity set will consist of all subjects who receive at least 1 dose of study drug, have 
an ADA status assessment at baseline, and at least 1 postbaseline sample.
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, Apfel Risk Score, sex, ethnicity, and race). 
Individual subject demographic and baseline characteristics data will be listed.
13.1.3
Efficacy Analysis
The primary and secondary efficacy analyses and summaries will be based on the FAS. Sensitivity 
analyses based on the PPAS will also be performed for primary and secondary efficacy endpoints. 
Unless otherwise stated, all efficacy analyses will be based on estimation approach using a 2-sided 
CI with an α of 20% and 5% respectively. Formal hypothesis testing will not be performed.
To evaluate the impact of the identified dosing errors at some participating sites, additional 
sensitivity analyses may be performed in the Safety Analysis Set by the actual treatment received.
Primary Efficacy Analysis: For the primary efficacy endpoint, complete responders 6 hours post 
surgery in the TAK-951 and ondansetron groups, along with the treatment difference in 
proportions, will be estimated and the associated 2-sided 80% and 95% CIs calculated. The point 
estimate of the treatment difference between TAK-951 and ondansetron and the associated CIs 
will be based on the Cochran-Mantel-Haenszel method, adjusting for the number of Apfel risk 
factors. In the event that the number of responders or nonresponders in either treatment group is 
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too small (ie, ≤5), the exact method (eg, Clopper-Pearson CI for proportions in each treatment
group and exact unconditional confidence limits for treatment difference) will be performed 
instead. Subjects who are missing data needed to determine endpoint status will be considered as 
treatment failures. 
Subgroup analyses by the number of simplified Apfel risk factors (3 or 4) and postoperative opioid 
analgesics usage (yes or no) for the primary endpoint will be performed using the statistical 
methods used for the primary efficacy analysis. Point estimates and the associated 80% CI and 95% 
CI for the true treatment difference between TAK-951 and ondansetron will be presented for the 
subgroups.
Secondary Efficacy Analysis: The binary secondary endpoints include: emesis in the first 6 hours 
and within 24 hours post surgery, absence of nausea in the first 6 hours and within 24 hours post 
surgery, requiring rescue therapy for breakthrough PONV within 24 hours postsurgery, and total 
response within 24 hours post surgery, will be analyzed similarly to the primary efficacy endpoint. 
The peak nausea VRS score at 30 minutes and 1, 2, 6, and 24 hours after completion of surgery in 
subjects will be analyzed using a mixed-effect model repeated measures (MMRM). This MMRM 
model will include treatment, the number of Apfel risk factors, timepoint, and 
treatment-by-timepoint interaction as fixed effects, and subject as a random effect. Point estimates 
and the associated 80% CI and 95% CIs for treatment difference between TAK-951 and 
ondansetron by timepoint will be presented. The time from the end of surgery to the first emetic 
event endpoints will be analyzed using the Cox proportional hazards model. Point estimate and 
associated 80% and 95% CIs for the hazard ratio for TAK-951 versus ondansetron will be 
provided.
Exploratory Efficacy Analysis: The binary exploratory endpoints will be analyzed similarly to 
the primary efficacy endpoint.
13.1.4
PK Analysis
No formal noncompartmental PK analyses will be performed on concentration-time data. 
Summary statistics of plasma concentrations will be summarized using the PK set. Individual
concentration-time data will be included in listings only. 
A population PK and exposure-response analysis for efficacy and safety endpoints may be 
conducted as deemed necessary by sponsor, 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
DNA Analysis
The DNA measurements data will be analyzed separately, and a separate report will be prepared.
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13.1.6
Immunogenicity Analysis
Immunogenicity will be summarized using the immunogenicity set. Descriptive statistics will be 
used to summarize subjects in the following categories: ADA negative, ADA positive, low or high 
ADA titer.
The relationships among immunogenicity status (ADA and ADA titer), PK, and safety may be 
explored. Further details will be provided in the SAP.
13.1.7
Safety Analysis
Safety data being collected in a double-blinded fashion will be summarized using the Safety 
Analysis Set and will include AEs, clinical safety laboratory tests, vital signs, ECG parameters, 
and weight. Subjects who are ineligible to receive the second dose of study drug (ie, TAK-951 or 
matching TAK-951 placebo) due to failure to meet the vital sign requirements outlined in 
Section 6.1 be unblinded to the investigator; their safety data collected will be summarized 
separately.
13.1.7.1
AEs
The definition of treatment-emergent AEs will be provided in the SAP. AEs will be coded using 
MedDRA and will be summarized by SOC 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.
13.1.7.2
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 
techniques. Values outside normal ranges and potentially clinically significant values will be 
flagged and tabulated.
13.2
Interim Analysis and Criteria for Early Termination
The interim safety reviews will be conducted by the external DMC.
An interim analysis for futility based on the primary efficacy endpoint may be conducted based on 
Bayesian predictive probability after approximately 50 subjects have received both doses of 
double-blind study drug/matching placebo before surgery and during surgery and then have either 
completed all study procedures or withdrawn from the study. The purpose of this interim analysis 
is to assess the mechanism of action of TAK-951 in human subjects. Statistical simulations will be 
conducted based on the observed interim data to determine the Bayesian predictive probability of 
achieving certain desired complete response rate at 6 hours after administration of TAK-951 using 
the FAS. To evaluate the impact of the identified dose errors in investigational product volume at 
some sites, additional descriptive analyses for primary and selected secondary and/or exploratory 
efficacy endpoints may be performed for both treatment arms to aid the internal decision-making. 
There is no plan to evaluate stopping for overwhelming efficacy in this study.
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The interim analysis will be performed by a firewalled unblinded reporting team in a manner that 
maintains the study blind to the investigators, site staff, and study subjects. Given that this is a 
sponsor-open study, the interim safety and efficacy review results will be presented to the DMC 
and reviewed by the sponsor but remain blinded to the investigators, site staff, blinding monitoring 
personnel, and study subjects. The DMC will indicate to the sponsor whether futility criteria have 
been met. 

Stop the study for futility if the Bayesian predictive probability of achieving a complete 
response rate at 6 hours of at least 30% meets the prespecified stopping rule for futility (futility 
is nonbinding).
Exploratory data-driven analysis may be requested by the sponsor to identify safety concerns 
and/or efficacy of TAK-951 in subjects. The interim analysis may be used by the sponsor to assess 
the numbers of subjects that will be replaced.
Complete details related to the unblinding and analysis of the interim futility evaluation and 
interim safety and efficacy reviews will be described in the SAP, data access management plan, 
and in the DMC charter.
Other additional interim analysis of safety and/or efficacy may be conducted for sponsor internal 
decision-making and would be defined in the SAP.
13.3
Determination of Sample Size
The sample size was calculated based on primary efficacy analysis (ie, estimation of treatment 
difference with respect to the primary efficacy endpoint). Assuming true complete response rates 
at 6 hours of 60% and 80% in the ondansetron and TAK-951 groups, respectively, and given 
approximately 50 subjects per treatment group, the half width of a 2-sided 80% CI and a 2-sided 95% 
CI for treatment difference between TAK-951 and ondansetron in primary efficacy endpoint 
complete response rate at 6 hours will be approximately 11.5% and 17.5%, respectively, based on 
CIs using the normal approximation for the binomial distribution. This level of precision with the 
chosen sample size was considered acceptable for the statistical objective of this trial.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the (e)CRFs. 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 (CRO) and by the IRB. In the event a monitor cannot visit the site in a timely manner, 
alternative monitoring approaches, such as remote source verification or telephone contact may be 
used to ensure data quality and integrity and maintain patient safety.
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 
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Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of (e)CRFs and associated source documents. It is important that the 
investigator and other study personnel are available during monitoring visits and that sufficient 
time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB, as required). 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments. If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution 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 D. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRBs
The IRBs must be constituted according to the applicable state, federal, and local requirements of 
each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
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also be obtained. Those Americas sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, a copy of the informed consent form, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB for 
approval. The IRB’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug or study specific activity). The IRB approval must refer to 
the study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent form) reviewed; and state the approval date. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation and, 
when applicable, the sponsor has received permission from competent authority to begin the study. 
Until the site receives drug/notification, no protocol activities, including screening, may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports, and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
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 before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
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It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject 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 before the subject enters into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a DNA sample for analysis can withdraw their consent and 
request disposal of a stored sample at any time before analysis. The sponsor must be notified of 
consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical 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 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, Food and Drug Administration [FDA], Medicines and Healthcare 
products Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s 
designated auditors, and the appropriate IRBs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
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study participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
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 sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
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.
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16.0
REFERENCES
1. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for 
predicting postoperative nausea and vomiting: conclusions from cross-validations between 
two centers. Anesthesiology 1999;91(3):693-700.
2. Tateosian VS, Champagne K, Gan TJ. What is new in the battle against postoperative nausea 
and vomiting? Best Pract Res Clin Anaesthesiol 2018;32(2):137-48.
3.
4.
5.
6. Hingorani P, Karnad DR, Rohekar P, Kerkar V, Lokhandwala YY, Kothari S. Arrhythmias 
seen in baseline 24-hour Holter ECG recordings in healthy normal volunteers during phase 1 
clinical trials. J Clin Pharmacol 2016;56(7):885-93.
7. Min SS, Turner JR, Nada A, DiMino TL, Hynie I, Kleiman R, et al. Evaluation of ventricular 
arrhythmias in early clinical pharmacology trials and potential consequences for later 
development. Am Heart J 2010;159(5):716-29.
8. Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient satisfaction after 
anaesthesia and surgery: results of a prospective survey of 10,811 patients. Br J Anaesth 
2000;84(1):6-10.
9. Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, et al. Consensus guidelines 
for the management of postoperative nausea and vomiting. Anesth Analg 2014;118(1):85-113.
10. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al. A factorial trial of six 
interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 
2004;350(24):2441-51.
11. Kranke P, Bergese SD, Minkowitz HS, Melson TI, Leiman DG, Candiotti KA, et al. 
Amisulpride prevents postoperative nausea and vomiting in patients at high risk: a randomized, 
double-blind, placebo-controlled trial. Anesthesiology 2018;128(6):1099-106.
12.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
n
ive nau
ve nau
erkar V,
rkar V
recordin
record
16;56(7
6;56(
DiMino T
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DL, H
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13.
14. Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. Fourth consensus 
guidelines for the management of postoperative nausea and vomiting. Anesth Analg 
2020;131(2):411-48.
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ensus
lg


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17.0
APPENDICES
Appendix A
Schedule of Study Procedures
Day -28 to 1
Day 1
Day 14±2
Screening
Before
Surgery
During
Surgery
Postsurgery 
Observational 
Period
Hospital Discharge 
/ET
Follow-up 
Visit
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
X
Medication history
X
X
Concomitant medications/therapies
X
X
X
X
X
X
Simplified Apfel Risk Score
X
Physical examination 
X
Height, weight, BMI
X
Vital signs (HR, BP, and RR) a
X
X
X
X
X
Body temperature a
X
X
X
Serum or urine pregnancy test (hCG) b
X
X
FSH b
X
HBsAg and anti-HCV
X
Clinical laboratory evaluations (hematology and 
serum chemistry) c
X
X
X
12-lead ECG d
X
X
X
X
Telemetry d
X
X
Randomization to treatment
X
Administration of study drug for prophylaxis a, e
X
X
Assessment of anesthesia and surgical procedure 
time f
X
Assessment of nausea g
X
X
Assessment of emetic events h
X
X
AE assessment 
X
X
X
X
X
X
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Day -28 to 1
Day 1
Day 14±2
Screening
Before
Surgery
During
Surgery
Postsurgery 
Observational 
Period
Hospital Discharge 
/ET
Follow-up 
Visit
Plasma sample for TAK-951 PK i
X
X
X i
Buccal epithelial cells sample for DNA 
X
Serum sample for immunogenicity j
X
X
X
BMI: body mass index; BP: blood pressure; ECG: electrocardiogram; (e)CRF: electronic case report form; ET: early termination; FSH: follicle-stimulating 
hormone; 
 HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV: hepatitis C virus; HR: heart rate; 
HRQOL: health-related quality of life; IV: intravenous; PACU: postanesthesia care unit; PK: pharmacokinetic; RR: respiratory rate; SC: subcutaneous.
a Vital signs (HR, BP) will be collected in duplicate and averaged at all time points. Vital signs will be collected at screening, before dosing with ondansetron or 
matching ondansetron placebo (ie, before surgery), immediately before dosing with TAK-951 or matching TAK-591 placebo (ie, during surgery), and at the end of 
surgery (ie, wound closure) and recorded in the (e)CRF. See Section 6.1 for eligibility to receive study drug/matching placebo based on predefined vital sign criteria 
for cardiovascular stability. During surgery, vital signs will be monitored continuously for safety purposes. RR will also be collected at these same timepoints. Vital 
signs will also be collected in the immediate postsurgical period, see Section 9.1.5 for additional postsurgical details. Body temperature will also be taken before 
surgery and approximately 8 and 24 hours postsurgery.
b Women of child-bearing potential must be confirmed negative for pregnancy by serum hCG at screening and by urine hCG the day of surgery, before dosing. See 
Section 9.1.10.3 for details. 
c Clinical laboratory evaluations (hematology and serum chemistry) do not need to be repeated on the day of surgery if the screening assessments were performed 
within 2 weeks, did not show any clinically relevant abnormalities, and were discussed with the medical monitor. 
d ECGs will be monitored continuously by telemetry during surgery and for the first 24 hours post surgery. A standard 12-lead ECG will be performed at screening, 
on Day 1 before surgery, on admittance to the PACU (approximately 1 hour post dose), and before hospital discharge or as needed if symptoms or abnormalities in 
the telemetry. See Section 9.1.12 for details. 
e TAK-951 or TAK-951 placebo will be administered approximately 30 to 45 minutes before end of surgery (wound closure) in eligible subjects (see Section 6.1). 
Ondansetron 4 mg IV or ondansetron IV placebo will be administered immediately before induction of anesthesia.
f Anesthesia time will be assessed from anesthesia induction until extubation. Surgery time will be defined as the time from incision to the end of wound closure.
g The presence and severity of subject-reported nausea anytime during the 24-hour follow-up period will be recorded by the site staff. Nausea will also be assessed 
by direct questioning by the site staff at 30 minutes and 1, 2, 6, and 24 hours post surgery, and results will be recorded (see Appendix B).
h Time and number of emetic events (vomiting and/or retching) will be noted (see Appendix C). Assessment of emetic events should occur during postsurgical 
observational period up to 24 hours ±30 minutes postsurgery.
i PK samples should be collected according to sampling time windows after dosing presented in Table 9.c. The fifth PK sample during the 22- to 26-hour window 
may coincide with hospital discharge.
j Sample for immunogenicity is collected before surgery (baseline), at discharge/early termination, and at the follow-up visit.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Appendix B
Verbal Rating Scale (VRS) for Nausea
Please rate the severity of your nausea (desire to vomit without the presence of expulsive muscular 
movements) using the scale below, where 0 represents “no nausea” and 10 represents the “worst 
nausea possible.” 
Date and Time of assessment:
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Appendix C
Emetic Events
Please contact the site staff immediately for assistance in case of emesis.
Emesis is defined as vomiting (the forceful discharge of even the smallest amount of stomach 
contents) or retching/dry-heaves (the same muscular movements as vomiting but without 
expulsion of stomach contents).
To be filled out by the subject or site staff.
Date and time of emetic event(s): (mark each check box as applicable)
□Vomiting
□Retching 
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Appendix D
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 before 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 Code of Federal Regulations (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 in 21 CFR Part 50, ICH, and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix E
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
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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
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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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 last dose. 
Regular pregnancy tests will be performed throughout the study for all female subjects of 
childbearing potential. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 30 days after 
last dose. If the partner or wife of the subject is found to be pregnant during the study, the 
investigator will offer the subject the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix F
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 G
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up
Investigators must be vigilant for abnormal liver test results in subjects during the clinical trial. 
Transient fluctuations in serum aminotransferases occur commonly in clinical trial subjects, but it 
is crucial that the investigator identifies and evaluates subjects with possible hepatic injury. This 
guidance is intended to aid investigations of abnormal liver test results in clinical trial subjects who 
had no known liver disease and had either normal or near normal baseline liver test results (ie, 
ALT <2 times the ULN, total bilirubin <1.5 times the ULN, and alkaline phosphatase <1.5 times 
the ULN) at the time of enrollment.
In evaluating trial subjects with abnormal liver test results, the investigator should perform 
follow-up laboratory tests to confirm the abnormal test results and monitor the subject. If the 
abnormal liver test results are confirmed, then the subject should be monitored and, if necessary, 
additional diagnostic tests should be performed as shown in Figure 17.a. Suggested hepatic 
investigations are listed in Table 17.a. Criteria for considering discontinuation of study drug are 
shown in Figure 17.b. 
Subjects with Combined Elevations in Aminotransferase and Bilirubin
If a subject has elevated ALT ≥3 times the ULN with concurrent elevated total bilirubin >2 times 
the ULN or elevated INR >1.5, the investigator must contact the medical monitor and Takeda trial 
clinician within 24 hours. Hepatic investigations as suggested in Table 17.a should be initiated. 
Any event of elevated ALT ≥3 times the ULN with concurrent elevated total bilirubin >2 times the 
ULN or elevated INR >1.5 for which an alternative etiology has not been identified must be 
reported as an SAE.
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Figure 17.a
Liver Test Abnormality Monitoring and Follow-up
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Table 17.a
Hepatic Investigation
Medical history 

Concomitant medications (including over-the-counter medications, such as 
acetaminophen and herbal supplements).

Medical conditions (eg, ischemia, hypotension, severe hypoxemia, congestive 
heart failure, sepsis). 

Alcohol intake. 

Hepatobiliary disorder.

Previous liver disease or metabolic syndrome (eg, obesity, insulin resistance, 
diabetes, or dyslipidemia).

Travel history.
Physical examination 
(symptoms, signs, and 
laboratory results)

General malaise, fatigue, nausea, or vomiting.

Right upper quadrant pain or tenderness, fever, jaundice, rash.

Eosinophilia >5%.
Hepatic/hepatobiliary 
imaging

Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging).
Viral hepatitis serology 

Hepatitis A antibody (total and IgM).

Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core 
antibody (IgM), hepatitis C antibodies.

Hepatitis E (IgG and IgM).

Consider PCR for hepatitis B, C, and E.

Consider Epstein-Barr virus serology (viral capsid antigen, nuclear antigen, 
early antigen).

Consider cytomegalovirus serology (IgG and IgM).
Autoimmune hepatitis 
serology

Antinuclear antibody.

Anti-smooth muscle antibody.

Anti-liver-kidney microsomal antibody. 
IgG: immunoglobulin G; IgM: immunoglobulin M; PCR: polymerase chain reaction.
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Figure 17.b
Liver Test Abnormalities: Considerations for Study Drug Discontinuation 
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Appendix H
Protocol History
Amendment History:
Date
Amendment 
Number
Amendment Type (for regional 
Europe purposes only)
Region
13 September 2021
Amendment 4
Substantial
Global
28 July 2021
Amendment 3
Substantial
Global
11 January 2021
Amendment 2
Substantial
Global
22 September 2020
Amendment 1
Substantial
Global
23 June 2020
Initial protocol
Not applicable
Global
Protocol Amendment 3 Summary of Changes
This document describes changes from the study protocol incorporating Amendment No. 3. The 
primary reason for this amendment is to clarify the scope of interim analysis due to dosing errors in 
investigational product volume identified at some study sites. Given dosing errors, the study is 
modified to sponsor-open to inform decision-making on the interim efficacy analysis and for 
oversight of the study. The study will remain blinded to investigators, study site staff, and subjects.
Associated updates to the efficacy analysis, interim analysis, criteria for discontinuation, and study 
drug blind maintenance have also been made.
Changes in Amendment 3:
1. The protocol title was updated because the study is modified to sponsor-open.
2. Added language to clarify that a maximum of 160 subjects will be randomized in this study and 
that the sample size may be adjusted to potentially increase the sample size to allow 
approximately 100 subjects who have received both doses of double-blind study 
drug/matching placebo dosed per protocol.
3. Updated clinical background to include final data from first-in-human (FIH) study 
TAK-951-1001.
4. Provided additional exploratory objective/endpoints.
5. Added language to modify the study to sponsor-open.
6. The description of the interim analysis was modified as described above.
7. Inclusion criterion 5 was updated for clarification and consistency between Section 2.0 Study 
Summary and Section 7.0 Selection and Discontinuation.
8. Inclusion criterion 6 was updated to clarify inclusion of subjects of nonchildbearing potential.
9. Language added to include additional sensitivity analysis.
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.
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Changes in Amendment 3:
Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Title page
Section 2.0 Study Summary
Wording “sponsor-open” was added 
to the protocol title.
The protocol title was updated because 
the study has been modified to 
sponsor-open.
Section 2.0 Study Summary
Added language to clarify the 
sample size.
To clarify that a maximum of 
160 subjects will be randomized in this 
study and that the sample size will allow 
approximately 100 subjects who have 
received both doses of double-blind 
study drug/matching placebo dosed per 
protocol. Provided flexibility in number 
of subjects dosed with ondansetron 4 mg 
to allow subjects not dosed per protocol 
to be replaced with 1:1 randomization.
Section 4.1.2 Clinical 
Background
Updated to include final data from 
FIH study TAK-951-1001.
To align with Investigator’s Brochure 
(IB) Edition 05 update.
Section 4.3 Benefit/Risk Profile
Updated to include final data from 
study TAK-951-1001 and modified 
the language for dose dependence of 
vital sign changes.
To align with IB Edition 05 update.
Section 2.0 Study Summary
Section 5.1.3 Exploratory 
Objective
Section 5.2.3 Exploratory 
Endpoints
Added exploratory objective/ 
endpoints.
To clarify that exploratory analysis will 
be conducted and to list those 
exploratory objective/endpoints.
Section 2.0 Study Summary
Section 6.1 Study Design
Changed the sentence “All subjects 
in the study will be required to 
receive general anesthesia, expected 
to last at least 1 hour from induction 
of anesthesia to wound closure” to 
“Only subjects undergoing elective 
surgery under general anesthesia 
that is expected to last at least 1 hour 
from induction of anesthesia to 
wound closure are eligible to 
participate in the study.”
To clarify that this description in 
Sections 2.0 and 6.1 is consistent with 
inclusion criterion #2 as described in 
Section 7.2.
Section 2.0 Study Summary
Section 6.1 Study Design
Section 8.4 Study Drug Blind 
Maintenance
Added language to modify the study 
to sponsor-open.
To clarify that given dosing errors, the 
study is modified to sponsor-open to 
inform decision-making on the interim 
efficacy analysis and for oversight of the 
study. The study will remain blinded to 
investigators, study site staff, and 
subjects.
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Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0 Study Summary
Section 6.1 Study Design
Addition of wording “if utilized.”
To clarify that anesthesia reversal, if 
utilized, will be accomplished with 
neostigmine and glycopyrrolate only.
Section 2.0 Study Summary
Section 6.1 Study Design
Section 13.2 Interim Analysis and 
Criteria for Early Termination
Language was updated for interim 
analysis.
To clarify that given the identified dose 
errors in investigational product volume 
at some sites, additional descriptive 
analysis for primary and selected 
secondary and/or exploratory efficacy 
endpoints may be performed for both 
treatment arms to aid the internal 
decision-making. 
Other additional interim analysis of 
safety and/or efficacy may be conducted 
and would be defined in the statistical 
analysis plan (SAP).
Section 6.2 Justification for Study 
Design, Dose, and Endpoints
The following text was removed: “A 
total of 128 subjects (96 in the SRD 
part and 32 in MRD part) had been 
enrolled in the TAK-951-1001 FIH 
study at the time this protocol 
amendment was written. The SRD 
data from the study have been 
unblinded to prepare a regulatory 
response and are summarized in 
Section 4.1.2. The MRD part of the 
study has completed in the clinic, 
but data remain blinded and the 
database has not been locked; a brief 
overview of blinded data is provided 
in Section 4.1.2.”
Removed TAK-951-1001 FIH study data 
from this section on study design as it is 
no longer relevant to this section, and 
prior protocol had preliminary data from 
the study, which was not complete. 
Overview of updated complete final data 
from this study is provided elsewhere in 
the protocol (Section 4.1.2).
Section 7.1 Inclusion Criteria
Term “planned” was added to 
inclusion criterion 5.
Update was made for clarification and 
consistency between Section 2.0 Study 
Summary and Section 7.0 Selection and 
Discontinuation.
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria
Inclusion criterion 6 was updated to 
include subjects of nonchildbearing 
potential.
To clarify intent that subjects of 
nonchildbearing potential are also 
eligible for the study.
Section 7.8 Procedures for 
Discontinuation or Withdrawal of 
a Subject
Language added to criteria for 
replacing subjects.
To clarify that subjects may be replaced 
as appropriate based on significant 
protocol deviations.
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Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 9.1.13.1 Collection of 
Blood/Plasma/Serum
Clarification added that plasma 
samples for pharmacokinetic (PK) 
analyses will be collected as per 
Table 9c.
The following sentence was 
removed: “However, only plasma 
samples from subjects receiving 
TAK-951 will be analyzed.” The 
remaining text was revised to 
explain that plasma samples may be 
analyzed for ondansetron 
concentration, and the results may 
be reported separately.
To clarify the intent for PK analysis.
Section 2.0 Study Summary
Section 13.1.3 Efficacy Analysis
Language added to include 
additional sensitivity analysis.
To clarify that additional sensitivity 
analysis to evaluate the dosing error may 
be performed for final analysis.
Section 13.1.3 Efficacy Analysis
Exploratory efficacy analysis added.
To clarify that exploratory efficacy 
analysis (binary exploratory endpoints) 
will be performed.
Section 13.1.4 PK Analysis
Text updated to state that 
exposure-response analysis for 
efficacy and safety endpoints may 
be conducted as deemed necessary 
by sponsor.
To increase the flexibility of 
population-level analyses.
Secion 14.1 Monitoring Visits
Text “due to COVID-19 pandemic” 
was removed.
To expand to allow remote source data 
verification in other settings as 
appropriate.
Protocol Amendment 2 Summary of Changes
This document describes the changes from the protocol incorporating Amendment No. 2. The 
primary reason for this amendment is to clarify eligibility prior to each study drug administration 
based on vital sign monitoring after randomization (ie, predefined heart rate [HR] and blood 
pressure [BP] criteria must be met prior to induction of anesthesia before surgery) to receive 
ondansetron or matching ondansetron placebo, and prior to wound closure (ie, during surgery) to 
receive TAK-951 or matching TAK-951 placebo. 
Associated updates to the exclusion criteria, criteria for discontinuation, defined statistical analysis 
sets, and interim analysis have also been made.
Changes in Amendment 2:
1. Updated the Responsible Medical Officer and approvers in Section 1.0.
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Study No. TAK-951-2001
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Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
2. Clarified and updated the vital sign criteria for study drug eligibility and the monitoring 
procedures to implement these criteria.
3. Provided criteria for discontinuation from the study based on vital sign requirements for 
eligibility to receive study drug. 
4. Added language to replace subjects who are discontinued due to vital sign criteria for study 
drug eligibility. Added unblinding procedures for subjects who are ineligible to receive study 
drug.
5. Clarified the timing of the interim analysis.
6. Revised and clarified an exclusion criterion that applies vital sign requirements to both 
enrollment (screening) and randomization.
7. Updated the definitions of the Full Analysis Set (FAS) and the Safety Analysis Set.
8. Removed the modified intent-to-treat (mITT) Analysis Set.
9. Updated the clinical background and justification for study design to include new data from the 
first in-human (FIH) clinical study TAK-951-1001.
10. Added clarification for efficacy and safety analyses regarding subjects who do not receive the 
second dose of study drug. 
11. Updated the list of study mitigations for risk management to align with the clarifications to the 
vital sign criteria for study drug eligibility. 
12. Clarified the vital sign measurement interval from a nonclinical study of TAK-951 and 
sevoflurane administration.
13. Added risk for potential QTc prolongation with rescue therapy for postoperative nausea and 
vomiting (PONV).
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.
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description 
Rationale 
1.
Section 1.1 Contacts
Section 1.2 Approval
Updated the Responsible Medical 
Officer and signatories.
A new clinical lead has been 
assigned to the study.
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TAK-951
Study No. TAK-951-2001
Page 101 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description 
Rationale 
2.
Section 2.0 Study 
Summary
Section 6.1 Study Design
Section 9.1.5 Vital Sign 
Procedure
Section 9.3.2 Day 1
Text added clarifying Day 1 study 
procedures and eligibility to receive 
both doses of study drug (ie, 
ondansetron or matching ondansetron 
placebo, and TAK-951 or matching 
TAK-951 placebo) based on BP and 
HR requirements. Figures illustrating 
the procedure for determining 
eligibility to receive TAK-951 or 
matching TAK-951 placebo based on 
BP and HR criteria have also been 
added to Section 6.1.
As TAK-951 and ondansetron 
should not be given to subjects 
with signs of cardiovascular 
instability, clarification on vital 
sign monitoring and 
administration of study drug has 
been added. The decision trees for 
BP and HR (Figure 6.a and 
Figure 6.b, respectively) provide 
further clarity to site personnel. 
3.
Section 2.0 Study 
Summary
Section 8.5 Unblinding 
Procedure
Language added for unblinding by the 
investigator when a subject is 
ineligible to receive the second dose of 
study drug (ie, TAK-951 or matching 
TAK-951 placebo) due to failure to 
meet vital sign requirements. A 
decision tree (Figure 8.a) for 
unblinding and whether or not the 
subject will be discontinued from the 
study was also added.
Subjects who do not receive the 
second dose of study drug due to 
failure to meet the vital sign 
requirements will be excluded 
from efficacy analyses (definition 
of FAS). To determine whether or 
not the subject will be 
discontinued from the study, the 
blind must be broken by the 
investigator.
4.
Section 2.0 Study 
Summary
Section 6.1 Study Design
Section 7.7 Criteria for 
Discontinuation or 
Withdrawal of a Subject
Section 7.8 Procedures for 
Discontinuation or 
Withdrawal of a Subject
Language added to criteria for 
discontinuation: All subjects who do 
not receive the first dose of study drug 
due to failure to meet the vital sign 
criteria, and all subjects who receive 
placebo as the first dose but do not 
receive the second dose of study drug 
(ie, TAK-951) due to failure to meet 
the vital sign criteria will be 
discontinued from the study. Subjects 
who receive ondansetron as the first 
dose but do not receive the second 
dose of study drug due to failure to 
meet the vital sign criteria will remain 
in the study per-protocol until 
completion or withdrawal from the 
study, but will be excluded from the 
FAS.
Subjects who do not receive the 
first or second dose of study drug 
due to failure to meet the vital sign 
requirements will be excluded 
from efficacy analyses (definition 
of FAS). These subjects will be 
replaced so efficacy analyses may 
be conducted on approximately 
100 subjects who have received 
both doses of double-blind study 
drug/matching placebo. To 
determine whether or not the 
subject will be discontinued from 
the study, the blind must be 
broken by the investigator (see 
above).
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TAK-951
Study No. TAK-951-2001
Page 102 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description 
Rationale 
5.
Section 2.0 Study 
Summary
Section 6.1 Study Design
Section 6.3.1 Criteria for 
Premature Termination or 
Suspension of the Study
Section 13.2 Interim 
Analysis and Criteria for 
Early Termination
Clarification that the interim analysis 
will be performed when approximately 
50 subjects have received both doses 
of study drug (ie, ondansetron or 
matching ondansetron placebo, and 
TAK-951 or matching TAK-951 
placebo) and have either completed or 
withdrawn from the study. Added that 
futility will be nonbinding.
Subjects who are ineligible to 
receive the second dose of study 
drug (ie, TAK-951 or matching 
TAK-951 placebo) due to failure 
to meet vital sign requirements 
will be unblinded to the 
investigator and therefore 
excluded from efficacy analyses 
(definition of FAS), including the 
interim analysis.
6.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Revised and clarified exclusion 
criterion 14.
BP and HR exclusion criteria for 
eligibility to receive study drug 
has been updated for clarity 
(safety reasons mentioned above). 
This criterion now applies to 
eligibility for enrollment 
(screening) in addition to 
eligibility for randomization.
7.
Section 2.0 Study 
Summary
Section 13.1.1 Analysis 
Sets
Analysis sets updated to clarify that the 
FAS and Safety Analysis Set will 
include only subjects who receive both 
doses of study drug (ie, ondansetron or 
matching ondansetron placebo, and 
TAK-951 or matching TAK-951 
placebo), before surgery and during 
surgery. The mITT Analysis Set has 
been removed.
The FAS and Safety Analysis Set 
were updated to accommodate the 
changes made above, which 
eliminated the need for the mITT 
Analysis Set. 
8.
Section 2.0 Study 
Summary
Section 13.1.7 Safety 
Analysis
Language was added for the safety 
analyses of subjects who are ineligible 
to receive the second dose of study 
drug (ie, TAK-951 or matching 
TAK-951 placebo) due to failure to 
meet vital sign requirements. These 
subjects will be unblinded to the 
investigator. Subjects who received 
ondansetron as their first dose of study 
drug will remain in the study
per-protocol until completion or 
withdrawal from the study; however, 
their safety data will be summarized 
separately.
To determine whether or not a 
subject who does not receive the 
second dose of study drug will be 
discontinued or remain in the 
study, the blind must be broken by 
the investigator. Once the blind is 
broken, subjects will not be 
included in the Safety Analysis 
Set.
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TAK-951
Study No. TAK-951-2001
Page 103 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description 
Rationale 
9.
Section 4.1.2 Clinical 
Background
6.2 Justification for Study 
Design, Dose, and 
Endpoints
Blinded safety overview from Part 3
(multiple rising dose [MRD]) of Study 
TAK-951-1001 added.
Part 3 of Study TAK-951-1001 
has recently completed, and 
blinded safety results have been 
included in this protocol 
amendment. 
10.
Section 4.3 Benefit/Risk 
Profile
Updated list of study mitigations for 
risk management. 
Clarification on vital sign 
monitoring and study drug 
eligibility have been added for the 
reasons mentioned above.
11.
Section 6.3.1 Criteria for 
Premature Termination or 
Suspension of the Study
Updated list of criteria for premature 
termination or suspension of the study 
to include substantial vital sign 
changes (including SAEs) considered 
by the investigator and/or sponsor to 
be related to TAK-951 study drug. 
Clarification on these postoperative 
BP and HR measurements were also 
added regarding when and how these 
SAEs should be reported.
For the reasons mentioned above, 
vital sign changes deemed related 
to TAK-951 that are potentially 
harmful to study subjects could 
result in termination of the study. 
12.
Section 7.3.1 Synergistic 
Effect When Combined 
With Propranolol and 
Sevoflurane
Clarification added regarding the BP 
and HR effects of TAK-951 in 
combination with propranolol or 
sevoflurane in dogs.
Based on the global vital sign 
clarifications (see safety reasons 
above), details regarding the vital 
sign interval in studies with dogs 
have been added. Unlike the 
6-hour interval between vital sign 
measurements from 8 to 24 hours 
postsurgery in this study, vital 
signs were collected every 4 hours 
in the referenced study in dogs. 
13.
Section 7.5 Rescue 
Therapy
Risk for potential QTc prolongation 
added.
When selecting rescue treatment 
for PONV, the potential for QTc 
prolongation should be 
considered. 
14.
Section 9.3.2 Day 1
Clarification added that plasma 
samples for PK analyses can be 
collected during surgery or in the 
postsurgery observational period for 
the first window (1 to 3 hours after 
subcutaneous administration of study 
drug). Reference was also made to 
Table 9.c for clarity on PK sampling.
Update was made for 
clarification, to avoid site 
confusion.
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Study No. TAK-951-2001
Page 104 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description 
Rationale 
15.
Appendix A Schedule of 
Study Procedures
Clarification on vital sign 
measurements prior to administration 
of both doses of study drug/matching 
placebo.
Updated to match changes made 
elsewhere to the protocol.
16.
Appendix H Protocol 
History
Protocol history appendix, detailing 
updates in Protocol TAK-951-2001 
Amendment 1.
Standard operating procedures of 
the sponsor require a protocol 
history appendix for all 
amendments beyond Amendment 
1. 
Protocol Amendment 1 Summary of Changes
This section describes the changes from the protocol incorporating Amendment No. 1. Results 
from completed nonclinical studies were added to the background.
Information and an exclusion criterion with beta blockers were added, given the hypothesized 
synergistic effects of these drugs with TAK-951. 
Changes in Amendment 1:
1. Updated the approvers in Section 1.2.
2. Updated nonclinical background with new nonclinical data.
3. Updated clinical background to include new data from first-in-human (FIH) study.
4. Revised benefit/risk profile to include new nonclinical and clinical safety data.
5. Added secondary endpoints and analyses for absence of nausea.
6. Removed physical examination from secondary endpoints.
7. Clarified criteria for premature termination of the study.
8. Added an exclusion criteria for subjects who may be allergic to rescue therapy.
9. Added an exclusion criteria for subjects on antihypertensive medications.
10. Modified exclusion criteria to exclude subjects with active hepatitis B.
11. Added new section 7.3 Potential Drug Interactions, Section 7.3.1 Synergistic Effect When 
Combined With Propranolol and Sevoflurane.
12. Added Section 7.5 for Rescue Therapy.
13. Revised parameters in vital sign monitoring procedures.
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Study No. TAK-951-2001
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Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
14. Clarified that subjects who are hepatitis B surface antigen (HBsAg)-positive are excluded from 
the study.
15. Clarified that urinalysis sample is for pregnancy testing only.
16. Modified clinical term for nonhormonal method of contraception.
17. Clarified that electrocardiogram (ECG) tracings are collected in the clinical database for all 
subjects, but only submitted to the sponsor in the event of serious adverse events (SAEs).
18. Added section for more information on potential drug interactions.
19. Clarified when Data Monitoring Committee (DMC) review will be conducted.
20. Updated definition of Full Analysis Set (FAS).
21. Added language in case sites are affected by the coronavirus disease 2019 (COVID-19) 
pandemic.
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.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Section 1.2 Approval
Updated the signatories.
A new clinical lead and clinical 
pharmacology lead has been assigned 
to the study.
Section 4.1.1 Nonclinical 
Background 
Revised Section 4.1.1 with new 
nonclinical data provided in the 
Investigator’s Brochure (IB) update.
To align with IB Edition 04 update.
Section 4.1.2 Clinical Background 
Revised Section 4.1.2 with new data 
from FIH study.
To align with IB Edition 04 update.
Section 4.3 Benefit/Risk Profile 
Added data on concomitant dosing.
Given the hypothesized mechanism 
of vasodilation leading to decreased 
blood pressure (BP) and increased 
heart rate (HR), there is potential to 
worsen hypotension with 
administration of these medications.
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Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Section 5.2.2 Secondary Endpoints 
Section 2.0 Study Summary 
Added endpoints for absence of 
nausea in the first 6 hours and within 
24 hours postsurgery.
Removed physical examinations as a 
secondary endpoint.
Added absence of nausea endpoints 
to include these assessments based 
on agency feedback.
Physical examination should not be 
listed as an individual secondary 
endpoint. Worsening of physical 
findings will be encompassed by 
reported adverse events, which are a 
secondary endpoint and detailed 
analysis will be performed.
Section 6.3.1 Criteria for Premature 
Termination of Suspension of the 
Study 
Modified the HR criteria for 
premature termination of the study.
Clarified that >30% change in BP 
and HR was intended to be used as 
stopping criteria during the operative 
period (while patients were under 
sedation) as recommended 
previously by expert consultants. 
Also clarified that reference time 
point of comparison for those 
changes should be the vital signs 
obtained during the operative period 
immediately before study drug (TAK 
951/matching placebo) is given.
Clarified the reference time points of 
vital sign comparisons for the >50% 
stopping rule.
Section 7.2 Exclusion Criteria 
Section 2.0 Study Summary 
Added exclusion criteria for subjects 
who may be allergic to rescue 
therapy.
To exclude subjects who may have 
an allergy or contraindication to the 
recommended and available rescue 
therapy.
Section 7.2 Exclusion Criteria 
Section 2.0 Study Summary
Added exclusion criteria for subjects 
who are unable to discontinue 
antihypertensives perioperatively 
before surgery, including beta 
blockers.
Updated exclusion criteria language 
for hepatitis B infection.
Given hypothesized mechanism of 
vasodilation leading to decreased BP 
and increased HR, there is potential 
to worsen hypotension with 
administration of these medications.
To exclude subjects with active 
hepatitis B (HBsAg positive).
Section 7.3 Potential Drug 
Interactions, 7.3.1 Synergistic Effect 
When Combined With Propranolol 
and Sevoflurane (new section)
Added new section to describe the 
potential for a synergistic effect of 
TAK-951 with beta blockers.
Given hypothesized mechanism of 
vasodilation leading to decreased BP 
and increased HR, there is potential 
to worsen hypotension with 
administration of these medications.
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Study No. TAK-951-2001
Page 107 of 108
Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Section 7.5 Rescue Therapy 
Added section to clarify 
recommendations for rescue therapy.
Added section to clarify 
recommendations for rescue therapy 
(ie, treatment of nausea and vomiting 
in the postoperative period) per 
Agency feedback.
Section 9.1.5 Vital Sign Procedure 
Section 9.3.1 Screening
Section 9.3.2 Day 1
Section 9.3.3 Hospital 
Discharge/Early Termination 
Appendix A Schedule of Study 
Procedures 
Added respiratory rate (RR) and 
body temperature to the list of vital 
signs measured.
Given the potential perioperative 
effects of anesthesia and surgery on 
RR and body temperature, these 
parameters will be added as safety 
assessments.
Section 9.1.9, Table 9.a Clinical 
Laboratory Tests 
Section 9.3.1 Screening
Appendix A Schedule of Study 
Procedures
Removed hepatitis B core antibody 
to align with updated exclusion 
criteria.
To align with exclusion criteria that 
subjects with active hepatitis B will 
be excluded from the study.
Section 9.1.9 Procedures for Clinical 
Laboratory Samples
Added language to clarify that 
urinalysis sample is for human 
chorionic gonadotropin (hCG) 
testing only.
To clarify that urinalysis is for 
pregnancy testing only.
Section 9.1.10.3 Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance 
Changed the term “bilateral tubal 
occlusion” to “bilateral tubal 
ligation.”
To clarify the correct clinical 
terminology for highly effective 
method of contraception should be 
listed as bilateral tubal ligation and 
not occlusion.
Section 9.1.12 ECG and Telemetry 
Procedure
Modified sentence regarding 
submitting the ECG tracings to the 
sponsor.
To clarify that ECG tracings are 
collected in the clinical database for 
all subjects but only submitted to the 
sponsor in the event of SAEs. All 
tracings will be available as a source 
document for review and verification 
by the sponsor.
Section 10.2.4.5 Potential Drug 
Interaction (new section)
Added new section to describe 
potential drug interactions with 
vasodilating agents.
Given hypothesized mechanism of 
vasodilation leading to decreased BP 
and increased HR, there is potential 
to worsen hypotension with 
administration of these medications.
Section 11.1 External DMC 
Modified language to clarify when 
DMC review will be conducted.
To clarify the timing of safety review 
and interim analysis.
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Study No. TAK-951-2001
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Protocol Incorporating Amendment No. 4
13 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Section 13.1.1 Analysis Sets 
Updated definition of FAS.
Updated definition of FAS to “all 
subjects who were randomized to 
treatment,” following the 
intent-to-treat principle.
Section 14.1 Monitoring Visits 
Added language to justify alternative 
monitoring methods in case of 
monitoring interruptions due to the 
pandemic.
To add language in the case sites are 
affected by COVID-19 pandemic.
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ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
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SAP_001.pdf: 
NCT Number:  NCT04557189
Title: A Randomized Double-Blind, Sponsor-Open, Double-Dummy, Proof of 
Concept Phase 2 Study to Evaluate the Efficacy and Safety of TAK-951 Versus 
Ondansetron in the Prophylaxis of Postoperative Nausea and Vomiting in High-Risk 
Subjects
Study Number: TAK-951_2001
Document Version and Date: Version 5 / 25 February 2022 
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Statistical Analysis Plan


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-951-2001
A Randomized Double-Blind, Sponsor-Open, Double-Dummy, Proof of Concept Phase 2 Study
to Evaluate the Efficacy and Safety of TAK-951 Versus Ondansetron in the Prophylaxis of 
Postoperative Nausea and Vomiting in High-Risk Subjects
TAK-951 Versus Ondansetron Prophylaxis for Postoperative Nausea and Vomiting in High-Risk 
Subjects
PHASE 2
Version: 5
Date: 25 February 2022
Prepared by:
Based on:
Protocol Version: Version/Amendment 4
Protocol Date: 13 September 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Proof
Proof o
f
Ondanse
Ondans
High
High-R
perative 
erativ
ts
HASE 2
ASE
V
Date
Dat
on:n:
Pro
P
: For No


TAK-951-2001
Statistical Analysis Plan version 5.0
Page 2 of 46
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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TAK-951-2001
Statistical Analysis Plan version 5.0
Page 3 of 46
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objective................................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................13
5.1
Primary Endpoint.....................................................................................................13
5.2
Secondary Endpoints ...............................................................................................13
5.3
Exploratory Endpoints .............................................................................................14
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................15
7.1.1
Efficacy Endpoint Definitions..........................................................................16
7.1.2
Definition of Study Days .................................................................................17
7.1.3
Definition of Study Visit Windows..................................................................17
7.1.4
Conventions for Missing Adverse Event Dates ................................................19
7.1.5
Conventions for Missing Concomitant Medication Dates.................................20
7.1.6
Methods for Handling of Missing Efficacy Data ..............................................21
7.2
Analysis Sets ...........................................................................................................21
7.3
Disposition of Subjects ............................................................................................22
7.3.1
Study Information............................................................................................22
7.3.2
Disposition of Subjects ....................................................................................22
7.4
Demographic and Other Baseline Characteristics.....................................................22
7.5
Medical History and Concurrent Medical Conditions...............................................23
7.6
Medication History and Concomitant Medications...................................................23
7.7
Study Drug Exposure and Compliance.....................................................................24
7.8
Efficacy Analysis.....................................................................................................24
7.8.1
Primary Efficacy Endpoint(s)...........................................................................24
7.8.2
Secondary Efficacy Endpoint(s).......................................................................25
7.8.3
Exploratory Efficacy Endpoint(s).....................................................................25
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7.8.4
Sensitivity Analysis .........................................................................................26
7.8.5
Subgroup Analysis...........................................................................................26
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................27
7.9.1
Pharmacokinetic Analysis................................................................................27
7.9.2
Pharmacodynamic Analysis.............................................................................27
7.10
Other Outcomes.......................................................................................................27
7.10.1
Immunogenicity...............................................................................................27
7.11
Safety Analysis........................................................................................................28
7.11.1
Adverse Events................................................................................................29
7.11.2
Clinical Laboratory Evaluations.......................................................................31
7.11.3
Vital Signs.......................................................................................................32
7.11.4
12-Lead ECGs.................................................................................................32
7.11.5
Safety Analysis for Subjects Ineligible to Receive TAK-951/Placebo ..............32
7.12
Interim Analysis ......................................................................................................33
7.12.1
Efficacy Endpoints ..........................................................................................34
7.12.2
Bayesian Predictive Probability for the 1st IA...................................................35
7.12.3
Interim Decision Rules ....................................................................................36
7.12.4
Multiplicity Adjustment...................................................................................37
7.12.5
Data to be Presented ........................................................................................37
7.13
Additional Analysis Related to COVID ...................................................................37
7.14
Changes in the Statistical Analysis Plan...................................................................38
8.0
REFERENCE................................................................................................................39
LIST OF IN-TEXT TABLES
Table 7.a
Analysis Window Convention for Day 1 Post-surgery VS Measurements 
(excluding temperature). ....................................................................................17
Table 7.b
Analysis Window Convention for Day 1 Post-surgery VS Measurements –
Temperature.......................................................................................................19
Table 7.c
List of subgroups of interest...............................................................................26
Table 7.d
List of Immunogenicity Category and Definitions..............................................28
Table 7.e
NCI CTCAE ......................................................................................................29
Table 7.f
Clinical Laboratory Tests...................................................................................31
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LIST OF IN-TEXT FIGURES
Figure 4.a
BP Criteria for TAK-951 or Matching TAK-951 Placebo Dosing.......................12
Figure 4.b
HR Criteria for TAK-951 or Matching TAK-951 Placebo Dosing......................12
Figure 4.c
Schematic of Study Design ................................................................................13
Figure 7.a
IA Data Flow .....................................................................................................36
LIST OF APPENDICES
Appendix A
AEs of Special Interest.......................................................................................40
Appendix B
Table, Figures, and Listings for the 1st IA..........................................................41
Appendix C
Table, Figures, and Listings for the 2nd IA ........................................................43
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values and Vital 
Sign Values........................................................................................................45
Appendix E
Criteria for Markedly Abnormal Values for Vital Signs......................................46
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3.0
LIST OF ABBREVIATIONS
Acronym
Definition
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CBL
change from baseline
CI
confidence interval
COVID
coronavirus disease
CRF
case report form
CRO
contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
ECG
electrocardiogram
(e)CRF
(electronic) case report form
FAS
Full analysis set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B virus surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HR
heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
Property of Takeda: For No
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Acronym
Definition
mITT
modified intent-to-treat
MMRM
mixed-effect model repeated measures
MRD
multiple rising dose
PACU
postanesthesia care unit
PD
pharmacodynamic
PK
pharmacokinetic
PONV
postoperative nausea and vomiting
PPAS
per-protocol analysis set
PT
preferred term
PTE
pretreatment event
SAE
serious adverse event
SAF
Safety analysis set
SBP
systolic blood pressure
SC
subcutaneous
SOC
system organ class
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
USPI
United States Prescribing Information
VRS
verbal rating scale
Vz,ss
volume of distribution during the terminal phase of steady state
VT
ventricular tachycardia
WOCBP
women of childbearing potential
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is: 
!
To assess the efficacy of a single-dose of TAK-951 compared with ondansetron to prevent 
postoperative nausea and vomiting (PONV) in the immediate postoperative period (within 
6 hours post-surgery) in high-risk subjects undergoing elective surgery under general 
anesthesia.
4.2
Secondary Objectives
The secondary objectives are:
!
To assess the efficacy of TAK-951 to prevent PONV up to 24 hours post-surgery compared 
with ondansetron.
!
To assess the pharmacokinetics (PK) of TAK-951 in subjects undergoing elective surgery 
under general anesthesia.
!
To assess the safety, immunogenicity, and tolerability of TAK-951 in subjects undergoing 
elective surgery under general anesthesia.
4.3
Exploratory Objective
The exploratory objective of this study is:
!
!
To assess the binary responses of complete response, emesis, and absence of nausea within 
the first 3 hours post-surgery and subjects requiring rescue therapy for breakthrough PONV 
within 3 and 6 hours post-surgery.
4.4
Study Design
This is a phase 2 randomized, double-blind, sponsor-open, double-dummy, proof-of-concept 
study designed to assess the efficacy of TAK-951 compared with ondansetron in the prophylaxis 
of PONV in high-risk subjects undergoing elective surgery under general anesthesia. The study 
will also assess the safety, immunogenicity, and tolerability of TAK-951 in subjects undergoing 
elective surgery under general anesthesia. This is a double-blind study; the investigator and 
subjects are blinded to treatment assignment. The study will be conducted sponsor-open. Sponsor 
discussions with investigators and within the study team will be conducted in a blinded manner 
(ie, no unblinded information will be communicated to blinded investigators, site staff or blinded 
study monitoring personnel).
Subjects aged ≥18 years with 3 or more risk factors for PONV who are undergoing elective 
surgery under general anesthesia will be screened for enrollment up to 28 days before surgery. 
Property of Takeda: For Non-Com
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To be enrolled into the study and randomized to study drug, subjects will be required to meet all 
inclusion criteria and none of the criteria for exclusion. Antiemetics, other than the study drugs, 
are prohibited within 24 hours before and up to 24 hours after surgery except for postoperative 
rescue therapy. Only subjects undergoing elective surgery under general anesthesia that is 
expected to last at least 1 hour from induction of anesthesia to wound closure are eligible to 
participate in the study. The anesthesia protocol will allow the use of premedication with 
midazolam or fentanyl. Induction will be accomplished with propofol. Nitrous oxide will not be 
permitted. Anesthesia will be maintained with either sevoflurane or desflurane, but total 
intravenous (IV) anesthesia or propofol infusions for maintenance of anesthesia will not be 
permitted. Neuromuscular blocking agents may be used at the discretion of the anesthesiologist. 
Reversal, if utilized, will be accomplished with neostigmine and glycopyrrolate. Intraoperative 
analgesia may be accomplished with fentanyl or sufentanil as indicated. Postoperatively, the 
analgesic regimen will be left to the discretion of the physician. Subject controlled analgesia and 
analgesic adjuncts, such as nonsteroidal anti-inflammatory drugs and pregabalin, are allowed. 
Intraoperative steroids will not be permitted.
On the day of surgery, eligible subjects with 3 or more PONV risk factors will be randomly 
assigned to either Treatment Group A to receive ondansetron placebo IV (administered in not 
less than 30 seconds, preferably over 2 to 5 minutes) immediately before induction of anesthesia 
[Zofran USPI] and prophylaxis with 4 mg TAK-951 SC approximately 30 to 45 minutes before 
the end of surgery (defined as wound closure) or Treatment Group B to receive 4 mg 
ondansetron IV (administered in not less than 30 seconds, preferably over 2 to 5 minutes) 
immediately before induction of anesthesia and TAK-951 saline placebo subcutaneous (SC) 
administered approximately 30 to 45 minutes before the end of surgery.
Study drugs will be dosed sequentially: ondansetron or matching ondansetron placebo prior to 
induction of anesthesia [ie, before surgery], and TAK-951 or matching TAK-951 placebo prior 
to wound closure [ie, during surgery]. After randomization to Treatment Group A or B, subjects 
must demonstrate eligibility based on HR, BP, and cardiovascular stability before administration 
of each dose of study drug; these post-randomization criteria for study drug treatment are in 
addition to exclusion criterion #14 which applies to subject eligibility for enrollment and 
randomization.
For subjects who have been randomized but have not yet received ondansetron or matching 
ondansetron placebo, all subjects must demonstrate average of duplicate measurements of (1) 
HR ≥55 and ≤100 bpm, (2) SBP ≥90 mm Hg, and (3) DBP ≥60 mm Hg prior to administration of 
ondansetron or matching ondansetron placebo at induction. Subjects who fail to meet these 
criteria should not receive ondansetron or matching ondansetron placebo and will be 
discontinued from the study. The corresponding decision to hold the dose and withdraw the 
subject should be recorded in the (e)CRF.
Immediately prior to administration of TAK-951 or matching TAK-951 placebo, all subjects 
must demonstrate average of duplicate measurements of (1) HR ≥55 and ≤100 bpm, (2) SBP ≥90 
mm Hg, and (3) DBP ≥60 mm Hg. If these gating criteria are not met, further assessment of BP 
and HR must be performed as follows to determine eligibility for TAK-951 or matching TAK-
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CONFIDENTIAL
951 placebo dosing (both HR and BP criteria must be met before proceeding with the second 
dose of study drug):
1. If the average SBP is <90 mm Hg or the average DBP is <60 mm Hg, then the average 
mean arterial pressure (MAP) should be measured and evaluated. If the average of 
duplicate measurements of MAP is ≥70 mm Hg, then dosing with TAK-951 or matching 
TAK-951 placebo may proceed. If the duplicate average MAP is <70 mm Hg, the 
anesthesiologist may reassess eligibility for dosing. During the next 15 minutes 
(reassessment period of up to 15 ±2 minutes), the MAP will be recorded from at least 3 
independent BP cuff cycle readouts; if the MAP is <70 mm Hg on 2 or more repeat 
assessments, TAK-951 or matching TAK-951 placebo should not be administered and the
corresponding decision to discontinue dosing should be recorded in the (e)CRF. If the 
MAP is ≥70 mm Hg during the 15-minute reassessment period and the MAP is not <70 
mm Hg on 2 or more repeat assessments, TAK-951 or matching TAK-951 placebo 
dosing may proceed. A categorical decision tree for determining TAK-951 or matching 
TAK-951 placebo dosing eligibility based on BP is provided in Figure 4.a.
2. If the average HR is <55 or >100 bpm, the anesthesiologist may reassess within the next 
15 minutes (reassessment period of up to 15 ±2 minutes). Although HR is continuously 
monitored, recorded HR(s) will align with the BP cuff readout (if BP is recorded, the 
same timepoint[s] will be used). If the HR is <55 or >100 bpm on 2 or more independent 
assessments during the 15-minute reassessment period, TAK-951 or matching TAK-951 
placebo should not be administered and the corresponding decision to discontinue dosing 
should be recorded in the (e)CRF. If the HR is ≥55 or ≤100 bpm during the 15-minute 
reassessment period and is not <55 or >100 bpm on 2 or more repeat assessments, TAK-
951 or matching TAK-951 placebo dosing may proceed. A categorical decision tree for 
determining TAK-951 or matching TAK-951 placebo eligibility based on HR is provided 
in Figure 4.b.
If there are signs suggestive of cardiovascular instability during surgery or the subject 
fails to meet the defined vital sign criteria above (as evaluated by the anesthesiologist), 
TAK-951 or matching TAK-951 placebo should not be administered and the 
corresponding decision to hold the dose and withdraw the subject should be recorded in 
the (e)CRF (see Section 7.7). Subjects who do not receive TAK-951 or matching 
TAK-951 placebo will be unblinded to the investigator; those who received placebo at 
induction of anesthesia as their first dose of study drug will be discontinued from the 
study, and those who received ondansetron will continue to be monitored and assessed to 
study completion per-protocol.
Subjects having 1 or more episodes of vomiting/retching or significant nausea, defined as nausea 
score ≥4 measured on a 0 to 10 verbal rating scale (VRS) after surgery, (0 = no nausea at all and 
10 = the worst nausea imaginable) or upon subject’s request, will receive rescue therapy as per 
local standard of care guidelines and be considered a treatment failure (see Appendix B of the 
protocol). 
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Subjects will be monitored for the occurrence of emesis and the occurrence and severity of any 
nausea within the first 24 hours after surgery. Emesis will include vomiting, defined as the 
forceful, discharge of even the smallest amount of stomach contents; or retching, defined as the 
same muscular actions as vomiting but without expulsion of stomach contents. Nausea will be 
defined as the urge to vomit without the presence of expulsive muscular movements. The subject 
will be questioned by the site staff about the severity of nausea using a subject-reported 0 to 
10 VRS, where 0 represents no nausea and 10 represents the worst nausea imaginable at 1, 2, 6, 
and 24 hours after completion of surgery (wound closure). Any spontaneous complaints of 
nausea by subjects will also be noted and assessed for severity. 
Subjects may be discharged 24 hours post-surgery after completion of all scheduled procedures. 
There will be a follow-up visit on Day 14±2 for assessment of concomitant medications, adverse 
events (AEs) and blood sample for immunogenicity assessment. 
An interim analysis (IA) for futility may be conducted after approximately 50 subjects have 
received both doses of double-blind study drug/matching placebo before surgery and during 
surgery and then have either completed all study procedures or withdrawn from the study. The 
study may be stopped if the Bayesian predictive probability calculated based on the interim data 
meets the prespecified stopping rule criteria for futility; otherwise in the absence of safety 
concerns, the study will continue without modification. Futility is nonbinding. Additional 
descriptive analysis for primary and selected secondary and/or exploratory efficacy endpoints 
may be performed for both treatment arms to aid the internal decision making. Other additional 
IA(s) of safety and/or efficacy may be conducted based on different data cut(s). Should sponsor 
decided to perform additional IA(s), the analysis details would be defined in a subsequent 
version of this SAP.
A maximum of 160 subjects may be randomized to allow approximately 100 subjects to receive 
both doses of double-blind study drug/matching placebo per protocol.
A schematic of the study design is included as Figure 4.c. A schedule of assessments is listed in
Appendix A of the protocol.
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CONFIDENTIAL
Figure 4.a
BP Criteria for TAK-951 or Matching TAK-951 Placebo Dosing
Figure 4.b
HR Criteria for TAK-951 or Matching TAK-951 Placebo Dosing
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CONFIDENTIAL
Figure 4.c
Schematic of Study Design
ADA: antidrug antibody; FU: follow-up; IV: intravenous; PACU: postanesthesia care unit; SC: subcutaneous. 
a Vital sign criteria must be met according to Figure 4.a and Figure 4.b for eligibility to receive second dose of study 
drug (ie, TAK-951 or matching TAK-951 placebo) during surgery, approximately 30 to 40 minutes before wound 
closure.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary efficacy endpoint is complete response in the immediate postoperative period 
(6 hours post-surgery), defined as no emesis (vomiting or retching) and no need for rescue 
therapy (indicated if vomiting/retching and/or nausea score ≥4 or upon subject’s request) 
(Yes/No).
5.2
Secondary Endpoints
The secondary endpoints are:

Complete response within 24 hours post-surgery (Yes/No).

Emesis in the first 6 hours post-surgery (Yes/No).

Emesis within 24 hours post-surgery (Yes/No).

Absence of nausea in the first 6 hours post-surgery (Yes/No).

Absence of nausea within 24 hours post-surgery (Yes/No).

Requiring rescue therapy for breakthrough PONV within 24 hours post-surgery (Yes/No).

Time from end of surgery to first emetic event (vomiting or retching). 

Peak nausea VRS score (0 = no nausea at all, and 10 = the worst nausea possible) at 
30 minutes and 1, 2, 6, and 24 hours after completion of surgery in subjects who have not 
required rescue therapy.

Total response within 24 hours post-surgery, defined as no emesis, no nausea (VRS <1), and 
no need for rescue therapy (Yes/No). 
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CONFIDENTIAL
!
TAK-951 individual plasma concentrations.
!
Safety.
–
Adverse events (AEs).
–
Vital signs.
–
ECG.
–
Laboratory values (hematology and chemistry).
–
Immunogenicity assessment (positive/negative ADA and titer).
5.3
Exploratory Endpoints
The exploratory endpoints are:
!
The following exploratory endpoints were added per protocol amendment 3 dated 28Jul2021.
!
Complete response within the first 3 hours post-surgery, defined as no emesis (vomiting or 
retching) and no need for rescue therapy (indicated if vomiting/retching and/or nausea score 
≥4 or upon subject’s request) (Yes/No).
!
Emesis within the first 3 hours post-surgery (Yes/No).
!
Absence of nausea within the first 3 hours post-surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 6 hours post-surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 3 hours post-surgery (Yes/No).
6.0
DETERMINATION OF SAMPLE SIZE
The sample size was calculated based on primary efficacy analysis (ie, estimation of treatment 
difference with respect to the primary efficacy endpoint). Assuming true complete response rates 
at 6 hours of 60% and 80% in the ondansetron and TAK-951 groups, respectively, and given 
approximately 50 subjects per treatment group, the half width of a 2-sided 80% CI and a 2-sided 
95% CI for treatment difference between TAK-951 and ondansetron in primary efficacy 
endpoint complete response rate at 6 hours will be approximately 11.5% and 17.5%, respectively, 
based on CIs using the normal approximation for the binomial distribution. This level of 
precision with the chosen sample-size was considered acceptable for the statistical objective of 
this trial.
7.0
METHODS OF ANALYSIS AND PRESENTATION
The final analysis will be performed after the final database lock at the end of the study (EOS). 
A blinded data review will be conducted before unblinding of subjects’ 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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CONFIDENTIAL
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4, or higher. 
No formal statistical testing will be performed. The statistical analysis will be based on the 
estimation approach. The CIs reported will be 2-sided 80% and 95%, unless stated otherwise. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by analysis visit. For the 
categorical variables, counts and percentages of each possible value will be tabulated. The 
denominator for the percentage will be based on the number of subjects in each treatment group 
(column total) unless otherwise specified. For continuous variables, the number of subjects with 
non-missing values, mean, median, SD, minimum, and maximum values will be presented.
All data will be descriptively summarized by treatment groups and overall respectively. 
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CONFIDENTIAL
7.1.1
Efficacy Endpoint Definitions
Endpoint
Definition
Complete response in the 
immediate postoperative period 
(6 hours post-surgery) (Yes/No)
Complete response is defined as no emesis (vomiting or retching) and no need 
for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or 
upon subject’s request) within 6 hours post-surgery.
Complete response within 24 
hours post-surgery (Yes/No)
Complete response is defined as no emesis (vomiting or retching) and no need 
for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or 
upon subject’s request) within 24 hours post-surgery.
Complete response within the 
immediate postoperative period 
(3 hours post-surgery) (Yes/No)
Complete response is defined as no emesis (vomiting or retching) and no need 
for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or 
upon subject’s request) within 3 hours post-surgery.
Emesis in the first 6 hours post-
surgery (Yes/No)
Emesis (vomiting or retching) within 6 hours post-surgery.
Emesis within 24 hours post-
surgery (Yes/No)
Emesis (vomiting or retching) within 24 hours post-surgery.
Emesis within the first 3 hours 
post-surgery (Yes/No)
Emesis (vomiting or retching) within 3 hours post-surgery.
Absence of nausea in the first 6 
hours post-surgery (Yes/No)
Absence of nausea is defined as VRS score <1 without any rescue medication 
taken within 6 hours post-surgery.
Absence of nausea within 24 
hours post-surgery (Yes/No)
Absence of nausea is defined as VRS score <1 without any rescue medication 
taken within 24 hours post-surgery.
Absence of nausea within the first 
3 hours post-surgery (Yes/No)
Absence of nausea is defined as VRS score <1 without any rescue medication 
taken within 3 hours post-surgery.
Requiring rescue therapy for 
breakthrough PONV within 24 
hours post-surgery (Yes/No)
Taking (or received) rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) within 24 hours post-surgery.
Requiring rescue therapy for 
breakthrough PONV within 6
hours post-surgery (Yes/No)
Taking (or received) rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) within 6 hours post-surgery.
Requiring rescue therapy for 
breakthrough PONV within 3
hours post-surgery (Yes/No)
Taking (or received) rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) within 3 hours post-surgery.
Time from end of surgery to first 
emetic event (vomiting or 
retching)
Time from the date/time of end of surgery to the date/time of first emetic event 
(vomiting or retching). If a subject did not have an emetic event within 24 hours 
post-surgery, they will be censored at 24 hours post-surgery or early 
termination whichever comes first. Units will be in hours.
Peak nausea VRS score (0 = no 
nausea at all, and 10 = the worst 
nausea imaginable) 
Max VRS score at each timepoint (30 minutes and 1,2,6 and 24 hours after end 
of surgery) in subjects who have not required rescue therapy (indicated if 
vomiting/retching and/or nausea score ≥4 or upon subject’s request).
Total response within 24 hours 
post-surgery (Yes/No)
Total response is defined as no emesis, no nausea (VRS <1), and no need for 
rescue therapy within 24 hours post-surgery.
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7.1.2
Definition of Study Days
Study Day 1 is defined as the day of randomization. Other study days are defined relative to the 
Study Day 1 with Day 2 being the day after, and Day -1 being the day prior to Study Day 1.
7.1.3
Definition of Study Visit Windows
Baseline is defined as the last non-missing measurement prior to the first dose of study drug. 
All data will be analyzed using the protocol defined nominal visits, unless otherwise stated. 
Analysis Window Convention for Post-surgery VS Measurements
The post-surgery VS data will be collected from the subject entering PACU until 24-hour post-
surgery by scheduled timepoints during Day 1 Post-surgery Observational Period. Given that 
such scheduled post-surgery timepoints are not collected on the eCRF, the timepoints will be 
derived based on the actual time for the VS assessment taken relative to the time for the subject 
entering the PACU during Day 1 Post-surgery Observational Period, including unscheduled VS 
assessment collected during this time period. 
The analysis timepoint windows for the post-surgery timepoints are defined by the middle point 
of the two consecutives scheduled timepoints. Unless otherwise states, if a subject has more than 
one timepoint with a VS assessment included within a window, the assessment closest to the 
target time will be used. In case of ties between observations located on different sides of the 
target time, the later assessment will be used. In case of ties located on the same side of the target 
day (i.e., more than one value for the same timepoint), the mean of the values will be used.
Table 7.a
Analysis Window Convention for Day 1 Post-surgery VS Measurements 
(excluding temperature).
Visit
Scheduled Timepoints
Target Time
Time Range: 
(if VS assessment time 
relative to the time subject 
entering PACU lies within the 
range)
Day 1 before surgery a
NA
NA
NA
Day 1 during surgery a
NA
NA
NA
Day 1 post surgery b
End of Surgery c
Prior to Extubation
Extubation
≤ 0
End of Surgery (After 
Extubation) d
After Extubation and on 
or before PACU admin 
time 
Extubation
>0 and on or before PACU 
admin time.
Every 15mins for 1hr post-
surgery
15 mins Post-Surgery
15 mins
>0 and ≤ 22.5 mins 
30 mins Post-Surgery
30 mins
>22.5 mins and ≤ 37.5 mins 
45 mins Post-Surgery
45 mins
>37.5 mins and ≤ 52.5 mins
1 hour Post-Surgery
60 mins
>52.5 mins and ≤ 75 mins
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Table 7.a
Analysis Window Convention for Day 1 Post-surgery VS Measurements 
(excluding temperature).
Visit
Scheduled Timepoints
Target Time
Time Range: 
(if VS assessment time 
relative to the time subject 
entering PACU lies within the 
range)
1.5 hours Post-Surgery
90 mins
>75 mins and ≤105 mins
Every 30mins 2-4hrs post-
surgery
2 hours Post-Surgery
120 mins
>105 mins and ≤135 mins
2.5 hours Post-Surgery
150 mins
>135 mins and ≤165 mins
3 hours Post-Surgery
180 mins
>165 mins and ≤195 mins
3.5 hours Post-Surgery
210 mins
>195 mins and ≤225 mins
4 hours Post-Surgery
240 mins
>225 mins and ≤270 mins
Every hour until 8hrs post-
surgery
5 hours Post-Surgery
300 mins
>270 mins and ≤330 mins
6 hours Post-Surgery
360 mins
>330 mins and ≤390 mins
7 hours Post-Surgery
420 mins
>390 mins and ≤450 mins
8 hours Post-Surgery
480 mins
>450 mins and ≤660 mins
Every 6hrs until 24hrs post-
surgery
14 hours Post-Surgery
840 min
>660 mins and ≤1020 mins
20 hours Post-Surgery
1200 min
>1020 mins and ≤1440 mins
Hospital discharge/Early 
termination a
NA
NA
NA
a Data will be taken from the corresponding CRF pages and analyzed based on protocol-defined nominal visits.
b Data will be taken from CRF page “Day 1 Postsurgery Observational Period” and unscheduled visits falling into 
the window. The analysis timepoints will be derived following the timepoint windowing convention.
c If there are multiple VS assessments within this window, the VS assessment immediately prior to extubation time 
will be selected. Otherwise, it will be set to missing. 
d If there are multiple VS assessments within this window, the VS assessment closest to the extubation time will be 
selected. Otherwise, it will be set to missing. If subject already has ‘End of Surgery’ timepoint, then ‘End of Surgery 
(After Extubation)’ will not be mapped.
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Table 7.b
Analysis Window Convention for Day 1 Post-surgery VS Measurements –
Temperature.
Visit
Scheduled 
Timepoints
Target Time
Time Range: 
(if VS assessment time relative to 
the time subject entering PACU lies 
within the range)
Day 1 before surgery a
NA
NA
NA
Day 1 post surgery b
8 hours Post-Surgery
480 mins
>0 and ≤960 mins
24 hours Post-Surgery
1440 min
>960 mins and ≤1560 mins 
Hospital discharge/Early 
termination a
NA
NA
NA
a Data will be taken from the corresponding CRF pages and analyzed based on protocol-defined nominal visits.
b Data will be taken from CRF page “Day 1 Postsurgery Observational Period” and unscheduled visits falling into 
the window. The analysis timepoints will be derived following the timepoint windowing convention.
7.1.4
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or serious adverse events (SAEs), a missing or incomplete onset date will be imputed 
according to the following conventions:
1. If an onset date is missing, the derived onset date will be calculated as the first non-missing 
valid date from the following list (in order of precedence):
–
First study drug date.
–
Consent date (for SAEs only).
2. If an onset date is incomplete, the derived onset date will be calculated following:
–
Missing day, but month and year present: the day will be imputed as the 1st of the month. 
If the first study drug dose occurs in the same month and year but after the imputed date, 
the derived onset date will be set equal to the first study drug date.
–
Missing day and month, but year present: the day and month will be imputed as the 30th
June of the year. If the first study drug dose occurs in the same year but after the imputed 
date, the derived onset date will be set equal to the first study drug date. If the EOS date 
occurs in the same year but before the imputed date, the derived onset date will be set 
equal to the first study drug date. 
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For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
1. If an end date is missing, the derived end date will be imputed the last assessment date. 
2. If an end date is incomplete, the derived end date will be calculated following:
–
Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2009 will be imputed as 28 February 2009) of the month. Missing day 
and month, but year present: the day and month will be imputed as the 31st December of 
the year.
7.1.5
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the case report form (CRF). 
However, in case of missing or partial information in these dates, the following rules will be used:
If the start date is unknown or partial:

If the day is missing, the start day will be the first day of the month.

If the month is missing, 
–
If the year is the same as the date of first dose of study drug, the start month will be the 
month of the dose first study drug.
–
If the year is not the same as the date of first dose of study drug, the start month will be 
January.

If the year is missing, the start year will be the minimum of the year of the first clinic visit or 
the year of the informed consent date.

If the entire start date is unknown, the start date will be the date of first study drug 
administration.
If the stop date is missing, partial or “ongoing:”

If the day is missing, the stop day will be the last day of the month reported.

If the month is missing, 
–
If the year is the same as the date of last assessment, the stop month will be the month 
during which the last assessment occurred.
–
If the year is not the same as the year of the last assessment, then the end month will be 
December.

If the year is missing, the stop year will be the year in which the last assessment occurred.

If the entire stop date is unknown or if the medication is “ongoing”, the stop date will be the 
date of last assessment.
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7.1.6
Methods for Handling of Missing Efficacy Data
The missing dichotomous efficacy data (eg, complete response in the immediate postoperative 
period) will be handled using the non-responder imputation method, ie, any subject with missing 
information for determination of endpoint status will be considered as having an undesirable 
outcome in the analysis. 
Missing data for longitudinal continuous endpoints will not be imputed but handled using a 
mixed-effect model repeated measures (MMRM) assuming missing at random (MAR) 
mechanism.
Missing data for time to event endpoints will not be imputed. 
Other missing data handling method may be explored.
7.2
Analysis Sets
The analysis sets used for analysis will include the following:
Full Analysis Set (FAS): The FAS will include all subjects who are randomized to treatment
and received both doses of double-blind study drug (ie, ondansetron or matching ondansetron 
placebo, and TAK-951 or matching TAK-951 placebo) before surgery and during surgery. 
Subjects will be analyzed according to their randomized treatment, regardless of whether they 
receive an investigational product that is different from that to which they were randomized.
Per-protocol Analysis Set (PPAS): The PPAS is a subset of the FAS. The PPAS will include all 
subjects who are in the FAS and do not violate the terms of the protocol in a way that would 
impact the study output significantly. All decisions to exclude subjects for the PPAS will be 
made prior to the unblinding of the study. Analyses using the PPAS will be provided as a 
sensitivity analysis. 
Safety Analysis Set (SAF): The SAF will include all subjects who were randomized to 
treatment and received both doses of double-blind study drug (i.e, ondansetron or matching 
ondansetron placebo, and TAK-951 or matching TAK-951 placebo) before surgery and during 
surgery. In safety summaries, subjects will be analyzed according to the treatment they actually 
received.
PK Set: The PK Set will consist of all subjects who receive study drug and have at least 
1 evaluable PK sample.
Immunogenicity Set: The Immunogenicity Set will consist of all subjects who receive at least 1 
dose of study drug TAK-951, have an ADA status assessment at baseline, and at least 1 
postbaseline sample.
All Randomized Set: The All Randomized Set will consist of all subjects who were randomized 
to treatment. 
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7.3
Disposition of Subjects
7.3.1
Study Information
General study information will be provided, including the date the first subject signed informed 
consent, the date of the last subject’s last visit/contact, the date of the last subject’s last visit for 
collection of data for primary endpoint, MedDRA version, WHO Drug version and SAS version
used for creating the datasets. 
7.3.2
Disposition of Subjects
Summary of the subject disposition will be summarized for each treatment group and overall, 
and will include the following:

Summary of screen failures using all subjects who were not randomized.

Summary of eligibility for randomization using all subjects who signed the informed consent
form.

Summary of study subjects randomized by site, geographic region using the All Randomized 
Set.

Summary of subjects for each pre-defined population using the All Randomized Set: all 
randomized set, full analysis set, per-protocol set, safety analysis set, PK set and 
Immunogenicity set.

Summary of subjects for each pre-defined population using the Safety Analysis Set: safety 
analysis set, PK set and Immunogenicity set.

Summary of subjects randomized but not treated, randomized but only received the first dose 
of study drug and ineligible to receive the second dose of study drug, completing study drug 
and completing study, and disposition of subjects based on the reasons for discontinuation of 
treatment and for failing to complete the study using the All Randomized Set and Safety 
Analysis Set. Significant protocol deviations will be summarized descriptively using the All 
Randomized Set.
When calculating percentages for the reasons for not being treated, the total number of subjects 
not treated by the study drug will be used as the denominator. When calculating percentages for 
the reasons for discontinuation, the total number of subjects who prematurely discontinued will 
be used as the denominator.
Supporting data listings for randomization scheme, screen failures, subject disposition, and 
significant protocol deviations will be provided. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics variables will be summarized by each treatment group 
and overall using the FAS.
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For continuous variables (age, weight, height, body mass index [BMI]), summary statistics (N, 
mean, SD, median, minimum, and maximum) will be generated. Height and weight will be 
measured wearing indoor clothing and with shoes off and will be measured at the screening visit 
only. Body mass index (BMI) is calculated using metric units with the formula provided below. 
Height is recorded in centimeters without decimal places. Weight is collected in kilograms (kg) 
with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height = 176 cm 
(1.76 meters) and weight = 79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2
The values should be reported to 1 decimal place by rounding. Thus, in the above example, BMI 
would be reported as 25.6 kg/m2. 
For categorical or ordinal variables (gender, ethnicity, race, Apfel risk score, Apfel risk factors, 
female reproductive system status, substance use), the number and percentage of subjects in each 
category will be presented. The Simplified Apfel Risk Score includes the 4 most relevant risk 
factors for PONV (female sex, history of PONV and/or of motion sickness, nonsmoking status, 
and postoperative use of opioids) that is currently used in clinical practice and research as a 
simple tool to identify subjects at higher risk of PONV.
Individual subject demographic and baseline characteristics data will be listed.
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 18 or higher) coding system. 
During the screening period and prior to surgery, a complete medical history will be compiled 
for each subject. The history will be summarized by system organ class (SOC), preferred term 
(PT) and by each treatment group and overall based on the Safety Analysis Set. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the screening examination according to the 
judgment of the investigator. The condition (ie, diagnosis) should be described and will be 
summarized by system organ class and preferred term based on the Safety Analysis Set.
Individual subject medical history and concurrent medical condition data will be listed.
7.6
Medication History and Concomitant Medications
During the screening period and prior to surgery, a complete medication history will be compiled 
for each subject. The medication history will be coded using WHO Drug and summarized by 
standardized medication name based on the Safety Analysis Set. 
Concomitant medication is any drug given in addition to the study drug. Concomitant 
medications will be coded using WHO Drug. The number and percentage of subjects taking 
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concomitant medications will be tabulated by standardized medication name WHO drug generic 
term in the Safety analysis set, and categorized as follows:

Concomitant medications that started and stopped prior to baseline.

Concomitant medications that started prior to and were ongoing at baseline and those that 
started after baseline.
Data listing(s) for medication history and concomitant medication will be provided.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all subjects
in the Safety Analysis Set. No other summary statistics for the extent of exposure to study 
investigational products or compliance calculations will be performed for this study. 
7.8
Efficacy Analysis
The primary efficacy analyses and summaries will be based on the FAS. Sensitivity analyses 
based on the PPAS will also be performed for primary and secondary efficacy endpoints. Other 
sensitivity analyses based on the SAF will also be performed for primary, secondary and 
exploratory endpoints Missing data will be handled according to Section 7.1.6.
Unless otherwise stated, all efficacy analyses will be based on estimation approach using a 2-
sided CI with an α of 20% and 5% respectively. Formal hypothesis testing will not be performed.
Data listings for primary and secondary efficacy endpoints will be provided.
7.8.1
Primary Efficacy Endpoint(s)
For the primary efficacy endpoint, the proportion of complete responders in first 6 hours 
post-surgery in the TAK-951 and ondansetron groups will be calculated with the corresponding 
2-sided 95% confidence interval using normal approximation. The treatment difference in 
proportions of complete responders in 6 hours post-surgery between TAK-951 and ondansetron 
will be estimated and the associated 2-sided 80% and 95% CIs calculated. Point estimate of the 
treatment difference between TAK-951 and ondansetron and the associated CIs will be based on 
the Cochran-Mantel-Haenszel (CMH) method, adjusting for the number of Apfel risk factors
(3 or 4). In addition, a 2-sided 40% CI of treatment difference in proportion of complete 
responders in 6 hours post-surgery between TAK-951 and ondansetron will be constructed as 
well for internal decision making. 
In the event that the number of complete responders or non-responders in either treatment group 
is too small (i.e., ≤5), the exact method [e.g., Clopper-Pearson CI for proportions in each 
treatment group and exact unconditional confidence limits for treatment difference (Chan and 
Zhang, 1999)] will be performed instead. Subjects with missing data to determine endpoint status 
will be considered as undesired treatment outcome (ie, non-responders).
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7.8.2
Secondary Efficacy Endpoint(s)
The binary secondary efficacy endpoints are
!
Complete response within 24 hours post-surgery (Yes/No), 
!
Emesis in the first 6 hours post-surgery (Yes/No),
!
Emesis within 24 hours post-surgery (Yes/No),
!
Absence of nausea in the first 6 hours post-surgery (Yes/No),
!
Absence of nausea within 24 hours post-surgery (Yes/No),
!
Requiring rescue therapy for breakthrough PONV within 24 hours post-surgery (Yes/No), 
and 
!
Total response within 24 hours post-surgery (Yes/No)
The secondary efficacy endpoints will be analyzed similarly to the primary efficacy endpoint. 
The peak nausea VRS score at 30 minutes and 1, 2, 6, and 24 hours after completion of surgery
will be analyzed using a mixed-effect model repeated measure (MMRM). This MMRM model
will include treatment, the number of Apfel risk factors, timepoint, and treatment-by-timepoint
interaction as fixed effects, and subject as a random effect with unstructured covariance structure 
for the observed data up to 24 hours after completion of surgery. Point estimates and the associated 
80% CI and 95% CIs for treatment difference between TAK-951 and ondansetron by timepoint 
will be presented. 
The time from the end of surgery to the first emetic event will be analyzed using the Cox 
proportional hazard model with treatment group and the number of Apfel risk factors as 
independent variables. Point estimate and associated 80% and 95% CIs for hazard ratio for 
TAK-951 versus ondansetron will be provided. Kaplan-Meier (KM) estimates by treatment 
groups as well as KM plot will be presented. Subjects without documented emetic event within 
24 hours post-surgery will be censored at 24 hours post-surgery. 
In addition, line charts for the following endpoints will be generated by treatment group:
!
Proportion of subjects with complete response in first 6 and within 24 hours post-surgery,
!
Proportion of subjects with no emesis in the first 6 and within 24 hours post-surgery, 
!
Proportion of subjects with absence of nausea in the first 6 and within 24 hours post-surgery, 
and
!
Peak nausea VRS score by timepoint up to 24 hours post-surgery. 
7.8.3
Exploratory Efficacy Endpoint(s)
DNA sampling is optional in this study and will only be performed for subjects who provide 
consent to participate in this assessment. The DNA measurements data will be analyzed 
postst-sur
su
to the p
to the
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nd 24 h
d measur
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separately. The results from DNA measurements data will not be included in the clinical study
report (CSR) but a separate report.
The following additional exploratory efficacy endpoints were added in the protocol amendment 3 
and will be included in the final analysis. These endpoints will be analyzed using the Full 
Analysis Set (FAS) in a similar way as the primary efficacy endpoint. 
!
Complete response within the first 3 hours post-surgery, defined as defined as no emesis 
(vomiting or retching) and no need for rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) (Yes/No).
!
Emesis within the first 3 hours post-surgery (Yes/No).
!
Absence of nausea within the first 3 hours post-surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 6 hours post-surgery (Yes/No).
!
Requiring rescue therapy for breakthrough PONV within 3 hours post-surgery (Yes/No).
7.8.4
Sensitivity Analysis 
To assess the robustness of the analysis for primary efficacy endpoint and secondary efficacy 
endpoints, the following sensitivity analysis will be performed:
!
The primary and secondary efficacy endpoint analysis will be repeated using the PPAS. 
!
In the event of unintentional unblinding after implementing the protocol amendment 2 
specified unblinding procedure due to ineligibility to receive the TAK-951 or matching 
TAK-951 placebo during surgery, additional sensitivity analysis may be performed to 
evaluate the impact of unintentional unblinding on the primary efficacy endpoint by
removing the subjects whose treatment assignment was unintentionally unblinded from the 
FAS.
!
To evaluate the identified dosing error at some sites, additional sensitivity analysis for the
primary and selected secondary and exploratory efficacy endpoints may be conducted in a 
similar way as primary efficacy endpoint using the SAF, in which subjects will be analyzed 
by the actual treatment they received (e.g., ondansetron, TAK-951 4 mg,
).
Additional sensitivity analysis may be performed as appropriate.
7.8.5
Subgroup Analysis
The subpopulations of interest are outlined in Table 7.c.
Table 7.c
List of subgroups of interest
Subgroup of Interest
Subgroup Categories
Apfel risk factor
3,4
Opioid analgesics usage
Yes, No
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t 3
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etching 
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Subgroup analyses by the number of simplified Apfel risk factors (3 or 4) and postoperative 
opioid analgesics usage (yes or no) for the primary endpoint will be performed in a similar way 
as the primary analysis of the primary efficacy endpoint using the FAS. The treatment effect in 
proportions by treatment groups and associated 95% confidence interval method will be provided 
for each subgroup. 

For Subgroup analyses by the number of simplified Apfel risk factors (3 or 4), point estimate 
of the treatment difference between TAK-951 and ondansetron and associated 80% and 95% 
confidence intervals using the normal approximation will be presented for each subgroup. 

For Subgroup analyses by postoperative opioid analgesics usage (yes or no), point estimate 
of the treatment difference between TAK-951 and ondansetron and associated 80% and 95% 
confidence intervals using the CMH method adjusting for the number of simplified Apfel 
risk factors (3 or 4) will be presented for each subgroup. 
In the event that the number of complete responders is too small (ie, ≤5), the exact method [ie, 
Clopper-Pearson CI for proportions in each treatment group and exact unconditional confidence 
limits for treatment difference (Chan and Zhang, 1999)] will be performed instead.
The results will be tabulated and the corresponding forest plots for the subgroup analyses will be 
presented as well.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
No formal noncompartmental PK analyses will be performed on concentration-time data. 
Summary statistics of plasma concentrations will be summarized using the PK set. Individual 
concentration-time data will be presented in a data listing. 
A population PK and exposure-response analysis for efficacy and safety endpoints may be 
conducted as deemed necessary by sponsor 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 
CSR and will be a standalone report.
7.9.2
Pharmacodynamic Analysis
Not applicable
7.10
Other Outcomes
7.10.1
Immunogenicity 
Immunogenicity will be summarized using the Immunogenicity Set. 
Immunogenicity results will be summarized using the number and percentage of subjects in the 
immunogenicity categories (Table 7.d) by treatment group and nominal timepoint where 
appropriate. In addition, the analysis of ADA prevalence (i.e., the number and proportion of 
subjects who are ADA positive, including being pre-existing ADA positive, at any timepoint 
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during the study) and ADA incidence (i.e., the number and proportion of subjects who are 
treatment emergent ADA positive or/and treatment-boosted ADA positive, excluding being pre-
existing ADA positive, during the study) will be presented by treatment arm. Missing ADA data 
will not be imputed.
Table 7.d
List of Immunogenicity Category and Definitions
Immunogenicity Category
Definition
ADA Negative
Subject who does not have positive ADA response at 
baseline and in all postbaseline assessments
ADA Positive
Subjects who have confirmed positive ADA status in 
baseline or at least 1 postbaseline assessments
Pre-existing ADA Positive

Subject who has positive ADA response in the 
baseline sample and none of the postbaseline 
samples, or

Subject who has positive ADA response in both 
baseline and postbaseline samples but the 
maximum titer of the postbaseline ADA is <4
times the baseline titer value.
Treatment-boosted ADA Positive

Subject who has positive ADA response in both 
baseline and postbaseline samples, and

The titer of the maximum postbaseline ADA is ≥4 
times that of the baseline titer value.
Treatment Emergent ADA positive

Subject who has negative ADA in baseline 
sample, and

Subject who has positive ADA response in any 
postbaseline assessment.
High ADA titer (for ADA positive only)
Subject who has at least 1 postbaseline ADA titer >16
Low ADA titer (for ADA positive only)
Subject whose postbaseline ADA titers are all ≤16
Relationship between subject level ADA Status (ADA Positive and ADA Negative) and other 
endpoints (PK concentration, Primary endpoint and Hypersensitivity Related Adverse Events) 
may be summarized, if deemed necessary.
All immunogenicity data will be provided in by-subject listings based on immunogenicity 
analysis set.
7.11
Safety Analysis
Safety data being collected in a double-blinded fashion will be summarized using the Safety 
Analysis Set with the actual treatment received (i.e., Ondansetron vs TAK-951). The analysis of 
safety endpoints will include AEs, clinical laboratory values, vital signs, ECG, and weight. No 
statistical inference will be made for safety analyses.
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Subjects who are ineligible to receive the second dose of study drug (i.e., TAK-951 or matching 
TAK-951 placebo) due to failure to meet the vital sign requirements outlined in Section 4.0 will
be unblinded to the investigator; their safety data collected will be summarized separately.
7.11.1
Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but before 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
A Treatment Emergent AE (TEAE) is defined as any AEs newly occurring or worsening from 
the first dose and 14 days after last dose of study drug. A Serious TEAE is defined as SAE newly 
occurring or worsening from the first dose to up to 14 days after last dose of study drug,
regardless of relationship to study drug. SAEs will also be collected from last dose of study drug
to EOS.
Adverse events (AEs) will be coded by MedDRA (version 24.1 or higher). The number and
percentage of subjects with TEAEs, serious TEAEs, and SAEs will be summarized by System 
Organ Class, High Level Term, and Preferred Term. AEs will also be summarized by intensity, 
and by relationship (causality) to study investigational product respectively. All AEs and SAEs 
collected in the database (including those starting prior to first dose of study drug) will be listed. 
Any other information collected (eg, relationship to study drug, action taken etc.) will be listed as 
appropriate.
The intensity of all AEs will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 5.0). AEs not listed by the NCI 
CTCAE will be graded as displayed in Table 7.e. 
Table 7.e
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.
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.
ADL: activities of daily living; AE: adverse event.
In summary, AEs will be summarized by each treatment group and overall using the Safety 
Analysis Set as follows:

Overview of TEAEs - number and percentage of subjects, number of events;
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
Pretreatment AEs by system organ class (SOC), high level term (HLT), and preferred term 
(PT) - number and percentage of subjects;

TEAEs by system organ class (SOC), high level term (HLT), and preferred term (PT) -
number and percentage of subjects;

Most frequent TEAEs by PT (sorted by frequency, occurring in 5% of subjects in any 
treatment arm) - number and percentage of subjects;

TEAEs by relationship to study drug and by SOC, HLT and PT - number and percentage of 
subjects;

TEAEs by intensity (toxicity grade) and by SOC, HLT and PT - number and percentage of 
subjects;

TEAEs for toxicity grade 3 or higher by relationship and by SOC, HLT and PT - number and 
percentage of subjects;

TEAEs leading to treatment discontinuation by SOC, HLT, and PT - number and percentage 
of subjects;

Serious TEAEs by SOC, HLT and PT - number and percentage of subjects;

Serious TEAEs by relationship to study drug and by SOC, HLT and PT - number and 
percentage of subjects;

Serious TEAEs by intensity (toxicity grade) and by SOC, HLT and PT - number and 
percentage of subjects;

TEAEs resulting in death by PT - number and percentage of subjects;

AEs of special interest (AESI) by SOC, HLT, and PT (see Appendix A) - number and 
percentage of subjects.
Key guidelines for determining the incidence of AEs are as follows: 

AEs with missing or unknown intensity will be considered as severe (or Grade 3). 

AEs with missing or unknown relationship to study drug will be counted as related. 

A subject with 2 or more AEs within the same level of the MedDRA term will be counted 
only once in that level.

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.

For the summary of TEAEs by SOC, HLT and PT and intensity (toxicity grade), if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be 
counted only once by the maximum toxicity grade 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 toxicity grade in that SOC.
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
In selected summaries, adverse events will be summarized by the number of events reported 
in addition to the number and percentage of subjects with events.
Data listings for TEAEs, TEAEs leading to study discontinuation, SAEs, deaths, and AESI will 
be presented. The AEs 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), treatment group and time of TAK-951 or Placebo, 
relationship to study procedure, TEAE,SOC, onset date, end date or whether the event was 
ongoing, duration, intensity, action taken concerning study drug, causality to study drug, the 
outcome, whether the adverse event was an SAE and whether the event was an AESI. 
7.11.2
Clinical Laboratory Evaluations
Blood samples for analysis of the Hematology, Serum Chemistry, Serum and Urine parameters 
are shown in following table:
Table 7.f
Clinical Laboratory Tests
Hematology
Serum Chemistry
Red blood cells
White blood cells
Hemoglobin
Hematocrit
Platelets
AST
ALT
Albumin
Alkaline phosphatase
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen (BUN)
GGT
Glucose 
Potassium
Sodium
Other:
Serum
Urine
Hepatitis panel, including HBsAg and anti-HCV
Immunogenicity
Female subjects only:
hCG (for pregnancy)
Female subjects only:
Beta hCG (for pregnancy) in female subjects of 
childbearing potential
FSH in female subjects for whom menopause is 
suspected
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; GGT: 
γ-glutamyl transferase; HBsAG: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV: hepatitis C 
virus.
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The analysis of the laboratory data will include parameters tabulation for each assessment visit 
by treatment group using the Safety Analysis Set, using the following:

Number of subjects with non-missing values (n),

Arithmetic mean,

Median,

Standard deviation (SD),

Minimum and maximum observed values (Min, Max).
For the post-baseline assessments, the summary will also include the change from baseline 
values. Subjects with markedly abnormal values for laboratory tests will be tabulated (see 
Appendix D for details).
Individual subject clinical laboratory data will be listed by timepoint.
7.11.3
Vital Signs
Vital signs, including heart rate, respiratory rate, systolic and diastolic blood pressure, weight
and temperature will be summarized descriptively by visit and timepoint for absolute values and 
change from baseline using the Safety Analysis Set. The visit will include Before Surgery, 
During Surgery, Day 1 Post-Surgery, and Hospital Discharge. There are multiple timepoints 
during Day 1 Post-Surgery Observational Period and such timepoints will be derived by applying 
the timepoint windowing convention as described in Section 7.1.3. Subjects with markedly 
abnormal values for vital signs values will be tabulated (see Appendix D for details).
Box plots for absolute value and change from baseline of vital signs by timepoint will also be 
generated. Individual subject vital signs data will be listed by timepoint.
7.11.4
12-Lead ECGs
ECG parameters including HR, RR interval, PR interval, QT interval, and QRS interval, and 
QTcF will be summarized descriptively by visit for absolute values and change from baseline 
using the Safety Analysis Set. Overall interpretation by visit will also be tabulated. 
Box plots for absolute value and change from baseline of ECG parameters by timepoint will also 
be generated. Values outside normal ranges and potentially clinically significant values will be 
flagged.
7.11.5
Safety Analysis for Subjects Ineligible to Receive TAK-951/Placebo
The following additional safety analysis will be performed for subjects who are ineligible to 
receive the second dose of study drug (ie, TAK-951 or matching TAK-951 placebo) due to 
failure to meet the vital sign requirements outlined in Section 4.0 and unblinded to the 
investigator. 

Overview of TEAEs - number and percentage of subjects, number of events;
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
Summary of subjects with markedly abnormal values for laboratory tests;

Summary of subjects with markedly abnormal values for vital signs values;

Data listing of subjects with ECG values outside normal ranges and potentially clinically 
significant values.
7.12
Interim Analysis
The interim safety reviews will be conducted by the external DMC.
1st IA:
The 1st IA for futility based on the primary efficacy endpoint may be conducted based on 
Bayesian predictive probability after approximately 50 subjects have received both doses of
double-blind study drug/matching placebo before surgery and during surgery and then have 
either completed all study procedures or withdrawn from the study. The purpose of this interim 
analysis is to assess the mechanism of action of TAK-951 in human subjects. Statistical 
simulations will be conducted based on the observed interim data to determine the Bayesian 
predictive probability of achieving certain desired complete response rate at 6 hours after 
administration of TAK-951 using the FAS. In order to evaluate the impact of the identified dose 
errors in investigational product volume at some sites, additional descriptive analysis for primary 
and selected secondary and/or exploratory efficacy endpoints may be performed for both 
treatment arms to aid the internal decision making. There is no plan to evaluate stopping for 
overwhelming efficacy in this study. 
If applicable, the interim futility analysis may be performed by a firewalled unblinded reporting 
team in a manner that maintains the study blind to the investigators, site staff, and study subjects. 
Given that this is a sponsor-open study, the interim safety and efficacy review results will be 
presented to the DMC and reviewed by the sponsor, but remain blinded to the investigators, site 
staff, and study subjects. 
The Sponsor will be informed by the DMC if the futility criteria have been met and decide 
whether to stop the study for futility if the Bayesian predictive probability of achieving a 
complete response rate at 6 hours of at least 30% meets the prespecified stopping rule for futility
(see Section 7.12.3 for details). Futility is nonbinding.
Exploratory data-driven analysis may be requested by the sponsor to identify safety concerns 
and/or efficacy of TAK-951 in subjects. The interim analysis may be used by the sponsor to 
assess the numbers of subjects that will be replaced.
Complete details related to the unblinding will be described in the data access management plan 
(DAMP) and DMC charter. 
2nd IA:
The 2nd interim analysis (IA) of safety, efficacy, and PK data will be conducted to support 
sponsor internal decision making. This 2nd IA will be based on the selected data from the study 
TAK-951-2001 once approximately 80 fully dosed subjects have received both doses of double-
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blind study treatment (i.e., TAK-951/placebo and Ondansetron/placebo) and completed their 14-
day safety follow-up. The statistical analyses of the selected clinical data of the TAK-951-2001 
will be used in this additional IA and will follow the statistical methodologies described in this 
SAP.
Complete details related to the unblinding will be described in the data access management plan 
(DAMP) and DMC charter
7.12.1
Efficacy Endpoints
1st IA:
The efficacy endpoint of interest for interim futility analysis is the primary efficacy endpoint, 
complete response in first 6 hours post-surgery. Complete response is defined as no emesis 
(vomiting or retching) and no need for rescue therapy (indicated if vomiting/retching and/or 
nausea score ≥4 or upon subject’s request) in the immediate postoperative period (6 hours 
post-surgery). 
The primary efficacy endpoint, complete response rate in the first 6 hours post-surgery, will be 
used to derive Bayesian predictive probability for interim decisions. 
Descriptive analysis for the primary efficacy endpoint and selected secondary and exploratory
efficacy endpoints will be performed in the FAS by randomized treatment (ondansetron vs 
TAK-951 4 mg) and in the SAF by actual treatment received (e.g., ondansetron, TAK-951 4 mg, 
separately:
!
Complete response within the first 6 hours post-surgery (Yes/No)
!
Emesis within the first 6 hours post-surgery (Yes/No).
!
Time from end of surgery to first emetic event (vomiting or retching). 
!
Complete response within the first 3 hours post-surgery (Yes/No)
!
Emesis within the first 3 hours post-surgery (Yes/No).
The interim efficacy data will be analyzed in a similar way as primary efficacy endpoint, 
including count, percentage, and 2-sided 40%, 80% and 95% CIs. 
2nd IA:
The 2nd IA will include the same primary, secondary, and exploratory efficacy endpoints as 
mentioned above for the 1st IA, however, additional secondary efficacy endpoints will also be 
included.
The following additional secondary endpoints will be included:
!
Complete response within 24 hours post-surgery (Yes/No), 
!
Emesis within 24 hours post-surgery (Yes/No),
!
Absence of nausea within 24 hours post-surgery (Yes/No),
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
Requiring rescue therapy for breakthrough PONV within 24 hours post-surgery (Yes/No), 
and 

Total response within 24 hours post-surgery (Yes/No)
The additional secondary efficacy endpoints of the 2nd IA will be analyzed in a similar way as 
the secondary efficacy endpoint of the 1st IA. 
The futility analysis will not be performed for the 2nd IA.
7.12.2
Bayesian Predictive Probability for the 1st IA
Only subjects in the FAS who were randomized to receive TAK-951 will be included in the 
interim futility analysis.
Statistical simulation will be conducted based on the observed interim data and simulated 
post-IA data to derive the Bayesian predictive probability of achieving a complete response rate 
at 6 hours of at least 30% (ie, ≥30%) in TAK-951 arm, using non-informative prior distribution 
Beta (1,1) assuming the number of complete responders at 6 hours post-surgery for TAK-951 
follows binomial distribution. See Figure 7.a for details of IA data flow.

Prior distribution of complete response rate at 6 hours post-surgery for TAK-951: 
~	(	, ), where a = 1 and b = 1.

Posterior distribution of complete response rate at 6 hours post-surgery based on the 
observed interim data from TAK-951: |~	(	 + ,  +  −).
where 

a = 1, b = 1;

r = number of complete responders observed at interim;

x = number of subjects randomized to TAK-951 in the FAS at interim;

N = planned total number of subjects randomized to TAK-951 in the FAS = 50; 

Number of subjects post-IA randomized to TAK-951 in the FAS = N – x = 50 – x.
1
1
)
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)
(
)
(
)
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,
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






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a
b
a
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a
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



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(	)() 	−1(1 −)−1~+	−1(1 −)+−−1.
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Statistical Analysis Plan version 5.0
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CONFIDENTIAL
Figure 7.a
IA Data Flow
7.12.3
Interim Decision Rules
1st IA:
The DMC will consider the following guidelines based on the Bayesian predictive probability for 
making recommendations at IA. 
The threshold for a futility decision rule will be a Bayesian predictive probability of treatment 
success less than 0.3 at the time of the futility analysis, where treatment success is defined as a 
complete response rate at 6 hours in TAK-951 arm of at least 30% at the end of study:

If the Bayesian predictive probability (complete response rate at 6 hours in TAK-951 ≥30%) 
<0.3, then terminate the study for futility.

If the Bayesian predictive probability (complete response rate at 6 hours in TAK-951 ≥30%) 
≥0.3, then continue the study as planned.
In addition to the above formal criteria, relevant safety data may be used to guide the potential 
modification of design of the study. The DMC may also recommend that the study be stopped 
because of concerns about the safety for the study participants. Potential modifications that the 
DMC can recommend at IA include:

Continue trial without modifications.

The trial has met prespecified criteria for futility.
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Any recommendation other than “continue trial without modifications” must be accompanied by 
justifications for the recommendations and other follow up requirements as deemed necessary.
The sponsor may or may not follow the recommendation of futility stopping.
2nd IA:
The 2nd interim analysis (IA) will primarily support DMC for safety monitoring and no formal 
decision rules for efficacy analyses will be applied.
7.12.4
Multiplicity Adjustment
1st IA:
The 1st IA is for futility analysis and aimed to aid the internal decision making. It does not 
intend to stop the study for overwhelming efficacy. Hence, no multiplicity adjustment is 
necessary for the final analysis.
2nd IA: 
The 2nd IA is aimed to aid the internal decision making. It does not intend to stop the study for 
overwhelming efficacy. Hence, no multiplicity adjustment is necessary for the final analysis.
7.12.5
Data to be Presented
1st IA:
A list of TLFs generated for the 1st IA are specified in the Appendix B.
2nd IA:
The 2nd IA will be based on the selected data from the study TAK-951-2001 once approximately
80 fully dosed subjects have received both doses of double-blind study treatment (i.e., TAK-
951/placebo and Ondansetron/placebo) and completed their 14-day safety follow-up. The list of 
TLFs to be generated for this planned 2nd IA are specified in Appendix C. Additional data-
summaries or listings requested by the DMC may be generated.
The analysis of immunogenicity data will not be conducted for the 2nd IA. However, it will be 
performed for the final analysis.
7.13
Additional Analysis Related to COVID
Depending on the prevalence of coronavirus disease (COVID) infections and illness in regions 
where the study is conducted, additional analysis may be performed to evaluate the impact of 
COVID on the efficacy and safety of all participating subjects, including but not limited to the 
following:

COVID related discontinuation, including discontinuation due to adverse events in light of 
COVID infection and discontinuation due to COVID-related reasons other than COVID-
infection (e.g., travel limitation, reduced site staff, etc.).
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
COVID related AEs, including preferred term that contains “COVID-19”, “SARS-CoV-2”, 
“SARS-CoV-2” and “Coronavirus”.

All SAEs in COVID infected subjects.

All protocol deviations related to COVID.

Data listing of all subjects affected by COVID-19 related study disruption, including subject 
ID, site ID, and description of how individual’s participation was altered.

Data listing of all subjects taking COVID-19 vaccine during the course of study, if data 
permits.

If any site is closed due to COVID, sensitivity analysis may be performed for primary 
efficacy endpoint by excluding all affected subjects from the closed site. 
7.14
Changes in the Statistical Analysis Plan 
SAP Version
Date
Revision History
1.0
6Oct2020
NA
2.0
16Feb2021
The following changes have been made in this version of SAP per Protocol 
Amendment 2 dated 11Jan2021:
–
updated study procedure, dosing eligibility, and IA timing in Section 
4.4;
–
updated the definitions for FAS and SAF, removed mITT population, 
and added All Randomized Set in Section 7.2;
–
updated the summary of subject disposition in Section 7.3.2;
–
removed the sensitivity analysis using the mITT in Section 7.8;
–
added potential additional sensitivity analysis in the event of 
unintentional unblinding in Section 7.8.4;
–
updated the safety analysis in Section 7.11; and
–
clarified the timing and analysis population for IA in Section 7.12.
The following additional changes were also made in this version of SAP:
–
added analysis window convention for post-surgery VS assessments 
collected during Day 1 Post-surgery Observational Period in Section 
7.1.3;
–
updated the immunogenicity analysis per ADA data availability in 
Section 7.10.1;
–
clarified the VS analysis in Section 7.11.3;
–
added box plots to ECG analysis in Section 7.11.4;
–
added additional data listing for subjects taking COVID-19 vaccine 
during the course of study in Section 7.13; and
–
removed VS markedly abnormality criteria for HR by revised clinical 
guideline in Appendix D.
3.0
10May2021
The following changes were made to this version of SAP:
-
added 5 additional exploratory efficacy endpoints in Sections 5.3 and 
7.1.1, and the associated analysis in Section 7.8.3;
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SAP Version
Date
Revision History
-
clarified the endpoint definition for “requiring rescue therapy” and 
“absence of nausea” in Section 7.1.1; 
-
clarified the analysis for summary of screening failure in Section 7.3.2;
-
clarified the potential DMC recommendation for interim futility 
analysis in Section 7.12;
-
clarified the analysis for COVID-19 related AEs in Section 7.13; and
-
updated TLFs for the 1st IA in Appendix B.
4.0
2Aug2021
The following changes were made to this version of SAP per Protocol 
Amendment 3 dated 28Jul2021:
-
updated the study to double-blind (sponsor-open) in cover page and 
Sections 4.4; 
-
updated the analysis windowing rule in Table 7.a;
-
added additional sensitivity analysis to evaluate the impact of dosing 
error for final analysis in Section 7.8.4;
-
added the reference for exact unconditional confidence limits for
treatment difference in Section 7.8 and Section 8.
-
clarified the PK analysis in Section 7.9.1;
-
updated the interim analysis by adding additional descriptive efficacy 
analysis to aid the internal decision making in Section 12; 
-
added additional IA efficacy tables in Appendix B.
5.0
22Feb 2022
The following changes were made to this version of SAP:
-
updated the definition of Immunogenicity Set in the Section 7.2
-
updated the definition of Screen Failures in Section 7.3.2 and align 
analysis sets used in the table shells
-
updated Section 7.8 as sensitivity analyses are also performed based on 
SAF
-
Replaced TAK-951 >4 mg by 
 in the Sections 7.8.4 and 
7.12.1
-
updated Section 7.10.1
-
updated the Section 7.12
-
added Appendix C for the tables to be generated for the 2nd IA
8.0
Reference 
Chan I. and Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999; 55(4) 1202-1209. 
;
.13
13; and
; an
s
Protocol
rotoco
en) in
) in co
c
Table 7.a
able 7
to evalu
evalu
7.8.4;
7.8.4;
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ncond
tion 7.8 a
on 7.8
s in Sect
in S
analysis 
nalys
e interna
inter
nalal IA
IA e
ca
nges wer
nges w
ed the de
ed the d
dated the
dated t
analy
analysis
si
upda
upd
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-
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Appendix A
AEs of Special Interest
Based on the mechanism of action of TAK-951, certain AESIs have been predefined. The 
categories of AESIs, are described below. AESI will be summarized by investigator-indicated 
AESI in the eCRF and derived-AESI per the MedDRA terms or definition below.
AESIs
MedDRA Terms or definitions
Injection site reaction
Injection Site Reaction (HLT)
Hypotension
Hypotension (PT)
Tachycardia 
Tachycardia (PT)
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Appendix B
Table, Figures, and Listings for the 1st IA
A separate document labeled as “DMC TLF shells” was summarized the interim futility analysis
report presentation details. The unblinded IA results were presented to the DMC.
Number
Table Title
Blinded
Unblinded
1
Demographics – FAS
Y
Y
2
Baseline Characteristics – FAS
Y
Y
3
Subject Disposition – All Randomized Set
Y
Y
4
Summary of Primary Efficacy Endpoint and Bayesian Predictive Probability 
Assessment in Subjects Randomized to TAK-951 – FAS
Y
Y
5
Overview of TEAEs – Safety Analysis Set
Y
Y
6
TEAEs by System Organ Class, High Level Term, and Preferred Term –
Safety Analysis Set
Y
Y
7
TEAEs by Maximum Toxicity Grade by System Organ Class, High Level 
Term, and Preferred Term – Safety Analysis Set
Y
Y
8
TEAEs Considered Related to Study Drug by System Organ Class, High Level 
Term, and Preferred Term - – Safety Analysis Set
Y
Y
9
Serious TEAEs by System Organ Class, High Level Term, and Preferred Term 
– Safety Analysis Set
Y
Y
10
Serious TEAEs Considered Related to Study Drug by System Organ Class, 
High Level Term, and Preferred Term – Safety Analysis Set
Y
Y
11
TEAEs Leading to Discontinuation by System Organ Class, High Level Term, 
and Preferred Term – Safety Analysis Set
Y
Y
12
Treatment-Emergent Injection Site Reaction Adverse Events by System Organ 
Class, High Level Term, Preferred Term and Treatment Group – Safety 
Analysis Set
Y
Y
13
Treatment-Emergent Hypotension Adverse Events by System Organ Class, 
High Level Term, Preferred Term and Treatment Group – Safety Analysis Set
Y
Y
14
Treatment-Emergent Tachycardia Adverse Events by System Organ Class, 
High Level Term, Preferred Term and Treatment Group – Safety Analysis Set
Y
Y
15
Listing of Treatment-Emergent Adverse Events Leading to Death – Safety 
Analysis Set
Y
Y
16
TEAEs of Toxicity Grade 3 or Higher by System Organ Class, High Level 
Term, and Preferred Term – Safety Analysis Set
Y
Y
17
Summary of Markedly Abnormal Lab Test: Hematology – Safety Analysis Set
Y
Y
18
Summary of Markedly Abnormal Lab Test: Serum Chemistry – Safety 
Analysis Set
19
Summary of Markedly Abnormal Vital Signs – Safety Analysis Set
Y
Y
20
Summary of 12-Lead ECG Parameters and Change from Baseline by Visit –
Safety Analysis Set
Y
Y
Additional efficacy tables for primary and selected secondary/exploratory efficacy endpoints were
provided.
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Number
Table Title
Blinded
Unblinded
21
Summary of Complete Responders in First 6 Hours Post-Surgery by 
Randomized Treatment Group – FAS
N
Y
22
Summary of Complete Responders in First 6 Hours Post-Surgery by Actual 
Treatment Received – Safety Analysis Set
N
Y
23
Summary of Emesis in First 6 Hours Post-Surgery by Randomized Treatment 
Group – FAS
N
Y
24
Summary of Emesis in First 6 Hours Post-Surgery by Actual Treatment 
Received – Safety Analysis Set
N
Y
25
Summary of Complete Responders in First 3 Hours Post-Surgery by 
Randomized Treatment Group – FAS
N
Y
26
Summary of Complete Responders in First 3 Hours Post-Surgery by Actual 
Treatment Received – Safety Analysis Set
N
Y
27
Summary of Emesis in First 3 Hours Post-Surgery by Randomized Treatment 
Group – FAS
N
Y
28
Summary of Emesis in First 3 Hours Post-Surgery by Actual Treatment 
Received – Safety Analysis Set
N
Y
29
Summary of Time from End of Surgery to First Emetic Event by Randomized 
Treatment Group – FAS
N
Y
30
Summary of Time from End of Surgery to First Emetic Event by Actual 
Treatment Received – Safety Analysis Set
N
Y
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-2001
Statistical Analysis Plan version 5.0
Page 43 of 46
CONFIDENTIAL
Appendix C
Table, Figures, and Listings for the 2nd IA
The unblinded IA results will be provided to the DMC.
Number
Table Title
Blinded
Unblinded
1
Demographics – FAS
Y
Y
2
Baseline Characteristics – FAS
Y
Y
3
Subject Disposition – All Randomized Set
Y
Y
4
Subject Disposition – Safety Analysis Set
Y
Y
5
Overview of TEAEs – Safety Analysis Set
Y
Y
6
TEAEs by System Organ Class, High Level Term, and Preferred Term –
Safety Analysis Set
Y
Y
7
TEAEs by Maximum Toxicity Grade by System Organ Class, High Level 
Term, and Preferred Term – Safety Analysis Set
Y
Y
8
TEAEs Considered Related to Study Drug by System Organ Class, High Level 
Term, and Preferred Term - – Safety Analysis Set
Y
Y
9
Serious TEAEs by System Organ Class, High Level Term, and Preferred Term 
– Safety Analysis Set
Y
Y
10
Serious TEAEs Considered Related to Study Drug by System Organ Class, 
High Level Term, and Preferred Term – Safety Analysis Set
Y
Y
11
TEAEs Leading to Discontinuation by System Organ Class, High Level Term, 
and Preferred Term – Safety Analysis Set
Y
Y
12
Treatment-Emergent Injection Site Reaction Adverse Events by System Organ 
Class, High Level Term, Preferred Term and Treatment Group – Safety 
Analysis Set
Y
Y
13
Treatment-Emergent Hypotension Adverse Events by System Organ Class, 
High Level Term, Preferred Term and Treatment Group – Safety Analysis Set
Y
Y
14
Treatment-Emergent Tachycardia Adverse Events by System Organ Class, 
High Level Term, Preferred Term and Treatment Group – Safety Analysis Set
Y
Y
15
Listing of Treatment-Emergent Adverse Events Leading to Death – Safety 
Analysis Set
Y
Y
16
TEAEs of Toxicity Grade 3 or Higher by System Organ Class, High Level 
Term, and Preferred Term – Safety Analysis Set
Y
Y
17
Summary of Markedly Abnormal Lab Test: Hematology – Safety Analysis Set
Y
Y
18
Summary of Markedly Abnormal Lab Test: Serum Chemistry – Safety 
Analysis Set
Y
Y
19
Summary of Markedly Abnormal Vital Signs – Safety Analysis Set
Y
Y
20
Summary of 12-Lead ECG Parameters and Change from Baseline by Visit –
Safety Analysis Set
Y
Y
Additional efficacy tables for primary and selected secondary/exploratory efficacy endpoints will be 
provided.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-2001
Statistical Analysis Plan version 5.0
Page 44 of 46
CONFIDENTIAL
Number
Table Title
Blinded
Unblinded
21
Summary of Complete Responders in First 6 Hours Post-Surgery by 
Randomized Treatment Group – FAS
N
Y
22
Summary of Complete Responders in First 6 Hours Post-Surgery by Actual 
Treatment Received – Safety Analysis Set
N
Y
23
Summary and Analysis of Complete Response Within 24 Hours Post Surgery 
by Randomized Treatment Group – FAS
N
Y
24
Summary and Analysis of Complete Response Within 24 Hours Post Surgery 
by Actual Treatment Received – Safety Analysis Set
N
Y
25
Summary of Emesis in First 6 Hours Post-Surgery by Randomized Treatment 
Group – FAS
N
Y
26
Summary of Emesis in First 6 Hours Post-Surgery by Actual Treatment 
Received – Safety Analysis Set
N
Y
27
Summary and Analysis of Emesis Within 24 Hours Post Surgery by 
Randomized Treatment Group – FAS
N
Y
28
Summary and Analysis of Emesis Within 24 Hours Post Surgery by Actual 
Treatment Received – Safety Analysis Set
N
Y
29
Summary and Analysis of Absence of Nausea Within 24 Hours Post Surgery 
by Randomized Treatment Group – FAS
N
Y
30
Summary and Analysis of Absence of Nausea Within 24 Hours Post Surgery 
by Actual Treatment Received – Safety Analysis Set
N
Y
31
Summary and Analysis of Rescue Therapy for Breakthrough PONV Within 24 
Hours Post Surgery by Randomized Treatment Group – FAS
N
Y
32
Summary and Analysis of Rescue Therapy for Breakthrough PONV Within 24 
Hours Post Surgery by Actual Treatment Received – Safety Analysis Set
N
Y
33
Summary and Analysis of Total Response Within 24 Hours Post Surgery by 
Randomized Treatment Group – FAS
N
Y
34
Summary and Analysis of Total Response Within 24 Hours Post Surgery by 
Actual Treatment Received – Safety Analysis Set
N
Y
35
Summary of Complete Responders in First 3 Hours Post-Surgery by 
Randomized Treatment Group – FAS
N
Y
36
Summary of Complete Responders in First 3 Hours Post-Surgery by Actual 
Treatment Received – Safety Analysis Set
N
Y
37
Summary of Emesis in First 3 Hours Post-Surgery by Randomized Treatment 
Group – FAS
N
Y
38
Summary of Emesis in First 3 Hours Post-Surgery by Actual Treatment 
Received – Safety Analysis Set
N
Y
39
Summary of Time from End of Surgery to First Emetic Event by Randomized 
Treatment Group – FAS
N
Y
40
Summary of Time from End of Surgery to First Emetic Event by Actual 
Treatment Received – Safety Analysis Set
N
Y
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-2001
Statistical Analysis Plan version 5.0
Page 45 of 46
CONFIDENTIAL
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values and 
Vital Sign 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
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
SI
--
>3x ULN
AST
SI
--
>3x ULN
GGT
SI
--
>3*ULN, if baseline is normal;
>2*baseline, if baseline is high 
abnormal
Alkaline phosphatase
SI
--
>3*ULN, if baseline is normal;
>2*baseline, if baseline is high 
abnormal
Total Bilibrubin
SI
--
>1.5*ULN, if baseline is normal;
>1.5*baseline, if baseline is high 
abnormal
Albumin
SI
<25 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
Glucose
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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-2001
Statistical Analysis Plan version 5.0
Page 46 of 46
CONFIDENTIAL
Appendix E
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Systolic blood pressure
mm Hg
<85
>140
Diastolic blood pressure
mm Hg
<50
>90
Body temperature
°C
<35.6
>37.7
°F
<96.1
>99.9
Heart rate
(traditional clinical consensus)
bpm
<60
>100
Respiratory Rate
breath per minute
<12
>16
BMI
<18.5
>25.0

Class 1: BMI of 30 to <35

Class 2: BMI of 35 to <40

Class 3: BMI of 40 or 
higher.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


  
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