Clinical trial NCT06768658
Conditions: Nausea and Vomitting
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-03-02; Completion date: 2023-01-09
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a study of TAK-951 in participants with cyclic vomiting syndrome (CVS).

The main aims of this study are as follows:

* To check for side effects from treatment with TAK-951.
* To learn how much TAK-951 participants can receive without getting side effects from it.
* To check how much TAK-951 stays in the blood over time to work out the best dose.
* The dose of TAK-951 will be checked to see how much stays in their blood over time.
* To see if it is possible to give treatment at home. Participants will be given TAK-951 injected just under the skin (subcutaneous or SC).

Detailed description:

Arms: arm 1: Participants will receive TAK-951 placebo-matching injection (Treatment A), subcutaneously, single dose on Day 1 in CVS Episode 1 (Period 1), followed by TAK-951 4 milligram (mg) (Treatment B), injection, subcutaneously, single dose, on Day 1 in CVS Episode 2 (Period 2), further followed by TAK-951 4 mg (Treatment B), injection, subcutaneously, single dose on Day 1 in CVS Episode 3 (Period 3), and further followed by TAK-951 placebo-matching injection (Treatment A), subcutaneously, single dose on Day 1 in CVS Episode 4 (Period 4). A washout period of at least 14 days will be maintained between each Period. arm 2: Participants will receive TAK-951 4 mg (Treatment B), injection, subcutaneously, single dose on Day 1 in CVS Episode 1 (Period 1), followed by TAK-951 placebo-matching injection (Treatment A), subcutaneously, single dose on Day 1 in CVS Episode 2 (Period 2), further followed by TAK-951 placebo-matching injection (Treatment A), subcutaneously, single dose on Day 1 in CVS Episode 3 (Period 3), and further followed by TAK-951 4 mg (Treatment B), injection, subcutaneously, single dose on Day 1 in CVS Episode 4 (Period 4). A washout period of at least 14 days will be maintained between each Period.
Interventions: intervention 1: TAK-951 intervention 2: TAK-951 Placebo
Intervention descriptions: intervention 1: TAK-951 subcutaneous injection. intervention 2: TAK-951 placebo-matching subcutaneous injection.

Protocol documents:
Prot_000.pdf: 
NCT Number: 
Title: A Randomized, Double-Blind, Placebo-Controlled Repeated Crossover Study to 
Evaluate the Safety and Tolerability of Intermittent Single Doses of TAK-951 in the 
Abortive Treatment of Subjects with Cyclic Vomiting Syndrome.
Study Number: TAK-951_1501
Document Version and Date: Amendment 1  19 November 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. 
Protocol


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled Repeated Crossover Study to Evaluate 
the Safety and Tolerability of Intermittent Single Doses of TAK-951 in the Abortive 
Treatment of Subjects With Cyclic Vomiting Syndrome.
Study Identifier:
TAK-951-1501
Compound:
TAK-951
Date:
19 November 2021
Version/Amendment 
Number:
1
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
19 November 2021
Amendment 1
Substantial
United States
20 July 2021
Initial protocol
Not applicable
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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Study ID TAK-951-1501
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................8
1.1
Protocol Amendment 1 Summary of Changes..........................................................14
2.0
STUDY SCHEMATIC..................................................................................................18
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................19
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Benefit/Risk Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Study Objectives......................................................................................................26
5.1.1
Study Primary Objective..................................................................................26
5.1.2
Study Secondary Objective..............................................................................26
5.1.3
Study Exploratory Objectives ..........................................................................27
5.2
Endpoints.................................................................................................................27
5.2.1
Primary Endpoint.............................................................................................27
5.2.2
The primary endpoint is the assessment of vital signs, laboratory values, and 
AEs. Secondary Endpoints...............................................................................27
5.2.3
Exploratory Endpoints .....................................................................................28
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
6.1
Study Design ...........................................................................................................29
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................33
6.2.1
Rationale of Study Design ...............................................................................33
6.2.2
Rationale for Dose...........................................................................................34
6.2.3
Rationale for Endpoints ...................................................................................34
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures ............34
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................34
6.4
Study Beginning and End/Completion .....................................................................35
6.4.1
Definition of Beginning of the Study ...............................................................35
6.4.2
Definition of End of the Study.........................................................................35
6.4.3
Definition of Study Discontinuation.................................................................35
6.4.4
Criteria for Premature Termination or Suspension of the Study........................35
6.4.4.1
Criteria for Premature Termination or Suspension of Study .....................35
6.4.4.2
Procedures for Premature Termination or Suspension of the Study ..........36
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6.4.4.3
Possible Changes to the Procedures to Address Interruptions due to 
Pandemic Outbreak..................................................................................36
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............37
7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................38
7.3
Excluded Medications, Supplements, Dietary Products............................................41
7.3.1
Caffeine...........................................................................................................41
7.3.2
Diet, Fluid and Activity ...................................................................................41
7.4
Rescue Therapy .......................................................................................................41
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................41
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................42
7.7
Subject Replacement................................................................................................43
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................43
8.1
Clinical Study Drug .................................................................................................43
8.1.1
TAK-951 .........................................................................................................43
8.1.2
Placebo............................................................................................................43
8.1.3
Clinical Study Drug Labeling ..........................................................................43
8.1.4
Clinical Study Drug Inventory and Storage......................................................44
8.1.5
Clinical Study Drug Blinding...........................................................................44
8.1.6
Randomization Code Creation and Storage......................................................44
8.1.7
Clinical Study Blind Maintenance/Unblinding Procedure.................................44
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs.............................44
9.0
STUDY PROCEDURES...............................................................................................45
9.1
Administrative Procedures.......................................................................................45
9.1.1
Informed Consent Procedure............................................................................45
9.1.1.1
Assignment of Screening and Randomization Numbers ...........................45
9.1.1.2
Study Drug Assignment...........................................................................45
9.1.2
Inclusion and Exclusion...................................................................................46
9.1.3
Medical History/Demography..........................................................................46
9.1.4
Concomitant Medications ................................................................................46
9.1.5
Medication Storage/Procedure Review ............................................................46
9.2
Clinical Procedures and Assessments.......................................................................47
9.2.1
Full Physical Exam..........................................................................................47
9.2.2
Height and Weight...........................................................................................47
9.2.3
BMI.................................................................................................................47
9.2.4
Vital Signs.......................................................................................................47
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9.2.5
12-Lead ECG...................................................................................................48
9.2.5.1
Screening and Safety ECG.......................................................................48
9.2.5.2
Telemetry ................................................................................................49
9.2.5.3
 Audio Data, Event Marker,
...............49
9.2.6
Study Drug Administration..............................................................................50
9.2.7
AE Monitoring ................................................................................................50
9.2.8
Efficacy/COA Measurement............................................................................50
9.2.8.1
Assessment of Nausea .............................................................................50
9.2.8.2
Assessment of Emetic Events ..................................................................50
9.2.8.3
Assessment of Abdominal Pain................................................................51
9.2.8.4
Assessment of Headache..........................................................................51
9.3
Laboratory Procedures and Assessments..................................................................51
9.3.1
Hematology.....................................................................................................51
9.3.2
Chemistry........................................................................................................52
9.3.3
Urinalysis ........................................................................................................52
9.3.4
Glucose ...........................................................................................................52
9.3.5
Diagnostic Screening .......................................................................................53
9.4
PK, Immunogenicity, and DNA Samples .................................................................53
9.4.1
PK Measurements............................................................................................54
9.4.2
Immunogenicity (ADA) Measurements ...........................................................54
9.4.3
DNA Measurements ........................................................................................54
9.4.3.1
Sample for DNA......................................................................................54
9.4.4
Confinement....................................................................................................55
9.5
Childbearing Status and Methods of Contraception..................................................55
9.5.1
Women of Childbearing Potential....................................................................55
9.5.2
Women of Nonchildbearing Potential ..............................................................55
9.5.2.1
Contraception for Women of Nonchildbearing Potential..........................55
9.5.3
Male Subjects and Their Female Partners.........................................................55
9.5.4
Definitions and Procedures for Contraception and Pregnancy Avoidance.........56
9.5.5
Pregnancy........................................................................................................58
9.6
Documentation of Screen Failure.............................................................................58
9.6.1
Documentation of Randomization....................................................................59
9.6.2
Monitoring Subject Treatment Compliance......................................................59
9.6.3
Schedule of Observations and Procedures........................................................59
9.6.4
Screening.........................................................................................................59
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.6.5
End of Treatment/End of Study Visit ...............................................................60
9.6.6
Poststudy Care.................................................................................................60
9.7
Biological Sample Retention and Destruction ..........................................................60
10.0
ADVERSE EVENTS ....................................................................................................60
10.1
Definitions and Elements of AEs .............................................................................60
10.1.1
SAEs ...............................................................................................................62
10.1.2
Special Interest AEs.........................................................................................63
10.2
AE Procedures.........................................................................................................63
10.2.1
Assigning Severity/Intensity of AEs ................................................................63
10.2.2
Assigning Causality of AEs .............................................................................63
10.2.3
Start Date.........................................................................................................64
10.2.4
End Date..........................................................................................................64
10.2.5
Pattern of AE (Frequency) ...............................................................................64
10.2.6
Action Taken with Study Treatment.................................................................64
10.2.7
Outcome..........................................................................................................64
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................65
10.2.8.1
Collection Period.....................................................................................65
10.2.8.2
Reporting AEs.........................................................................................65
10.2.8.3
Reporting SAEs.......................................................................................66
10.2.8.4
Management of Specific AEs...................................................................66
10.2.9
Safety Reporting to Investigators, IRBs or Independent Ethics Committees, 
and Regulatory Authorities ..............................................................................68
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................68
11.1
External DMC .........................................................................................................68
12.0
STATISTICAL METHODS..........................................................................................68
12.1
Statistical and Analytical Plans ................................................................................68
12.1.1
Analysis Sets ...................................................................................................68
12.1.1.1
Full Analysis Set......................................................................................68
12.1.1.2
Per Protocol Analysis Set.........................................................................69
12.1.1.3
Safety Analysis Set..................................................................................69
12.1.1.4
PK Set .....................................................................................................69
12.1.1.5
Immunogenicity Set.................................................................................69
12.1.2
Analysis of Demography and Other Baseline Characteristics ...........................69
12.1.3
Efficacy Analysis.............................................................................................69
12.1.4
Safety Analysis................................................................................................72
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12.1.4.1
AEs .........................................................................................................72
12.1.4.2
Clinical Laboratory Evaluation ................................................................72
12.1.4.3
Vital Signs...............................................................................................72
12.1.4.4
ECG ........................................................................................................72
12.1.4.5
Other Safety Parameters ..........................................................................73
12.1.5
PK Analysis.....................................................................................................73
12.1.6
Immunogenicity Analysis ................................................................................73
12.2
Interim Analysis and Criteria for Early Termination ................................................73
12.3
Determination of Sample Size..................................................................................74
13.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
13.1
Study-Site Monitoring Visits ...................................................................................74
13.2
Protocol Deviations..................................................................................................74
13.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
14.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
14.1
IRB and/or IEC Approval ........................................................................................75
14.2
Subject Information, Informed Consent, and Subject Authorization .........................76
14.3
Subject Confidentiality ............................................................................................77
14.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
14.4.1
Publication and Disclosure...............................................................................77
14.4.2
Clinical Trial Registration................................................................................78
14.4.3
Clinical Trial Results Disclosure......................................................................78
14.5
Insurance and Compensation for Injury....................................................................78
15.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................79
15.1
Administrative Information......................................................................................79
15.1.1
Study Contact Information...............................................................................79
15.1.2
INVESTIGATOR AGREEMENT ...................................................................80
15.1.3
Study-Related Responsibilities.........................................................................81
15.1.4
List of Abbreviations .......................................................................................81
16.0
DATA HANDLING AND RECORDKEEPING............................................................83
16.1
CRFs (Electronic)....................................................................................................83
16.2
Record Retention .....................................................................................................83
17.0
REFERENCES..............................................................................................................84
APPENDICES ..........................................................................................................................86
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Study ID TAK-951-1501
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LIST OF IN-TEXT TABLES
Table 10.a
NCI CTCAE ......................................................................................................63
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................18
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................86
Appendix B
Elements of the Subject Informed Consent.........................................................88
Appendix C
Investigator Consent to the Use of Personal Information ....................................91
Appendix D
Overview of Study Design for TAK-951-1501 Trial Embedded and Exit 
Interviews ..........................................................................................................92
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Study ID TAK-951-1501
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Compound:
TAK-951
Study Identifier: TAK-951-1501
Phase: 1b
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Repeated Crossover Study to Evaluate the Safety 
and Tolerability of Intermittent Single Doses of TAK-951 in the Abortive Treatment of Subjects With Cyclic 
Vomiting Syndrome.
Study Design:
This is a randomized, double-blind placebo-controlled repeated crossover study to evaluate the safety, tolerability, 
efficacy, pharmacokinetics (PK), and feasibility of episodic administration at home of TAK-951/placebo in subjects 
aged 18 to 50 years, inclusive, during the prodromal and early emetic phase in subjects with moderate to severe cyclic 
vomiting syndrome (CVS).
Study Primary Objective:
To evaluate the safety and tolerability of intermittent single subcutaneous (SC) doses of TAK-951 in subjects with 
moderate to severe CVS during the prodromal/early emetic phase at home.
Secondary Objectives:
!
To evaluate the efficacy of intermittent single SC doses of TAK-951 in subjects with CVS.
!
To assess the immunogenicity after intermittent single SC doses of TAK-951 in subjects with CVS.
Study Subject Population: Subjects with moderate to severe CVS based on the ROME IV diagnostic criteria, aged 
18 to 50 years, inclusive at screening.
Planned Number of Subjects:
Approximately 20 subjects
Planned Number of Sites:
Approximately 10 sites within the United States
Dose Levels:
 intermittent single dose
Route of Administration:
SC
Duration of Treatment:
Subjects completing the study will receive a single 
dose of either placebo or 
 TAK-951 in each of 4 
CVS episodes for a total of 2 doses of TAK-951 and 2 
doses of placebo over a 52-week period.
Planned Study Duration:
~18 months 
Main Criteria for Inclusion:
Subject eligibility is determined according to the following criteria before entry into the study: 
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements and is eligible for the study.
2.
The subject or, when applicable, the subject’s legally acceptable representative, signs and dates a written or 
electronic informed consent form and any required privacy authorization before the initiation of any study 
procedures.
3.
The subject is male or female and aged 18 to 50 years, inclusive. 
4.
The subject has at least a 1-year history of CVS diagnosis based on the Rome IV diagnostic criteria.
5.
The subject has had at least 4 CVS episodes over 6 months before screening during the last 12 months.
6.
If taking medications prescribed for the prophylaxis or abortive management of CVS, the subject must be 
receiving a stable dose for at least 3 months before screening.
7.
The subject is willing and able to exclusively use the protocol rescue medications if needed. 
8.
The subject has a stereotypic prodrome with onset ≤4 hours before CVS emetic phases.
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9.
The subject has a body mass index (BMI) between 18 and 32 kg/m2, inclusive.
10. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to 
use barrier method of contraception (eg, condom with or without spermicide) from signing of informed consent 
throughout the duration of the study and for 30 days after last dose OR a surgically sterile female subject, or 
females of nonchildbearing potential with laboratory confirmation of postmenopausal status (ie, 
follicle-stimulating hormone levels >40 mIU/mL) or one of childbearing potential who is sexually active with a 
nonsterilized male partner agrees to use a highly effective method of contraception from signing of informed 
consent throughout the duration of the study and for 30 days after the last dose as defined in Section 9.5.
Main Criteria for Exclusion:
Any subject who meets any of the following criteria will not qualify for entry into the study:
1.
The subject has participated in another interventional study within 4 weeks or 5 half -lives of the investigational 
study drug, whichever is longer, before the screening visit. The 4-week window will be derived from the date of 
the last study procedure and/or adverse event (AE) related to the study procedure in the previous study to the 
screening visit of the current study.
2.
The subject has potentially received TAK-951 in a previous clinical study, or has previously completed, 
discontinued, or withdrawn from this study.
3.
The subject is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or is unable to provide 
consent (eg, incapacity or potential duress or undue influence on informed consent process).
4.
The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an 
anaphylactic reaction or significant intolerance (including medication-induced emesis) to prescription or 
nonprescription drugs or food, or allergic reactions to allowed rescue medication(s).
5.
The subject has any condition or abnormality (including laboratory abnormalities), current or past, that, in the 
opinion of the investigator or medical monitor, would compromise the safety of the subject or interfere with or 
complicate the assessment of signs or symptoms of CVS.
6.
The subject uses medical or recreational cannabis more than 3 days/week or its usage triggers nausea and/or 
vomiting.
7.
The subject has a history of hypotension, autonomic instability, orthostatic hypotension (excluding in the context 
of concurrent dehydration), postural orthostatic tachycardia syndrome or a history or presence of 2 or more 
incidents of syncope within the last 5 years before screening.
8.
The subject has a history of long corrected QT interval (QTc) syndrome, history of significant cardia arrhythmia, 
or a history or presence of:
a)
A family history of unexplained sudden death or channelopathy; or
b)
Brugada syndrome (ie, right bundle branch block pattern with ST-elevation in leads V1-V3); or
c)
Second-degree atrioventricular block type 2, third degree atrioventricular block, prolonged QT interval with 
Fridericia correction method (QTcF) interval, hypokalemia, hypomagnesemia, or conduction abnormalities; 
or
d)
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT 
Syndrome); or
e)
Any clinically significant electrocardiogram (ECG) findings or medical history including: long or short 
QTcF (over 450 msec or less than 360 msec), bifascicular block or QRS ≥120 msec or PR interval >210 msec 
at screening; subjects with QTcF >450 msec (up to 470 msec) taking chronic tricyclic antidepressants (>3 
months) may be enrolled after consultation with the medical monitor or
f)
The subject has a documented history of sinus bradycardia (<45 beats per minute [bpm]), sinoatrial block, 
sinus pause ≥3 seconds, or sinus node dysfunction.
9.
The subject has a history of other cardiovascular or cerebrovascular disease as assessed by the investigator 
including: hypertension requiring therapy or a history or presence of diseases such as cardiac valvulopathy, 
myocardial infarction, stroke.
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Study ID TAK-951-1501
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10. The subject has average semirecumbent systolic blood pressure (SBP) <95 or >140 or a diastolic blood pressure 
(DBP) <65 mm Hg or >90 mm Hg at screening. Note: See Section 6.1 for specific cardiovascular criteria that 
must be met immediately before the dose for dosing eligibility.
11. The subject has a screening average heart rate (HR) <55 or >100 bpm; athletic subjects with a HR <55 bpm may 
be enrolled based upon the investigator’s judgement provided that HR is >45 bpm and rhythm is sinus 
bradycardia. Note: See Section 6.1 for specific cardiovascular criteria that must be met immediately before the 
dose for dosing eligibility.
12. The subject has orthostatic hypotension defined as a decrease in systolic BP ≥20 mm Hg or a decrease in diastolic 
BP ≥10 mm Hg after approximately 3 minutes of standing when compared with BP from the semirecumbent 
position, at screening. 
13. The subject has postural orthostatic tachycardia, defined as an increase of 30 bpm or HR >120 bpm after standing 
for approximately 3 minutes, at screening. 
14. The subject is taking medications commonly associated with tachycardia, palpitations, hypotension, or QTc 
prolongation as potential adverse effects (eg, beta blockers, nitrates, sildenafil).
15. The subject is taking medications prescribed for the prophylactic management of CVS with possible safety or 
tolerability interactions with TAK-951 as determined by the investigator(s). As above, chronic (>3 months) 
consistent doses of tricyclic antidepressants are allowed after consultation with the medical monitor if QTcF is 
<470. The use of prochlorperazine/or promethazine as a rescue medication is explicitly prohibited until >30 hours 
(5 half-lives of TAK-951) after IP administration.
16. Subject has a history of autonomic dysfunction. 
17. The subject has active neoplastic disease or history of neoplastic disease within 5 years of screening visit (except 
for basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix that has been 
definitively treated with standard of care approaches) and has received treatment in the last 5 years. 
18. The subject has a history of requiring emergency room/urgent medical treatment and intravenous fluid therapy for 
management of dehydration associated with clinically relevant hypotension for >2 CVS episodes in the last 6 
months.
19. The subject has a history of other conditions associated with episodic emesis including: type 1 diabetes mellitus, 
type 2 diabetes mellitus, gastroparesis, gastrointestinal dysmotility, inflammatory bowel disease, eosinophilic 
esophagitis, rumination, severe functional dyspepsia, severe gastroesophageal reflux disease, large (>3 cm) hiatal 
hernia, or unrepaired intestinal malrotation.
20. The subject has taken opiate medications for more than 3 days in the last month. 
21. The subject has a progressive neurological disorder or a structural disorder of the brain from birth, trauma or past 
infection.
22. The subject has an uncontrolled psychiatric disorder, to include history of suicide attempt, active major depressive 
disorder or severe panic disorder, or at the discretion of the investigator(s), for any clinically significant 
psychiatric history that would likely interfere with full participation in the study.
23. The subject has started a nonpharmacologic prophylactic approach (eg, acupuncture, biofeedback, chiropractic 
methods) within 1 month before initiation of the treatment period.
24. The subject has a history of substance abuse.
25. The subject has a positive pregnancy test or plans to become pregnant during the study period. 
26. The subject is a pregnant or lactating/nursing female.
27. The subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to TAK 951 (or any other 
glucose-dependent insulinotropic polypeptide receptor agonist investigational products) or to any other 
ingredients of the investigational product.
28. The subject has a clinically unstable disease or condition.
29. The subject has any disease or condition that could compromise the function of those body systems as assessed by 
the investigator that could result in altered absorption, excess accumulation, or impaired metabolism or excretion 
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Study ID TAK-951-1501
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CONFIDENTIAL
of the test medications (eg, mild, moderate or severe renal impairment [ie, estimated creatinine clearance <90 
mL/min, CrCL]) and/or altered hepatic function as assessed by the investigator (eg, alanine aminotransferase >2× 
the upper limit of normal [ULN], total bilirubin [TB]>1.5× ULN, alkaline phosphatase >1.5× ULN).
30. The subject has known or suspected active coronavirus disease 2019 infection as assessed by the investigator. 
Main Criteria for Evaluation and Analyses:
The primary objective of the study is safety and tolerability as assessed through primary endpoints of vital signs, 
laboratory assessments, and AEs.
The secondary endpoints exclude the first 30 minutes immediately following TAK-951/placebo administration. 
The following secondary endpoints will be assessed within 2, 4, and 8 hours postdose. 

Total response (Yes/No), defined as no emesis, no nausea (verbal rating scale [VRS] “none”) and no need for 
rescue therapy before each timepoint (by both electronic reported patient-outcomes [ePRO] and electronic 
observer-reported outcomes [eObsRO] inclusive). 

Absence of emesis (Yes/No), defined as no emesis and no need for rescue medication before each timepoint (by 
both ePRO and eObsRO).

Absence of significant nausea (Yes/No), defined as VRS of “none” or “mild”) and no need for rescue medication 
before the evaluation timepoint (ePRO).

Peak nausea VRS score at 0, 1, 2 hours in all subjects and 4, 8 hours postdose without receiving rescue medication 
before the evaluation timepoint (ePRO). Data will also be collected at 3, 5, 6, and 7 hours postdose as able.

Change in nausea VRS score at 1 and 2 hours in all subjects and 4, 8 hours postdose as compared with predose 
score without receiving rescue medication before the evaluation timepoint. Data will also be collected at 3, 5, 6, 
and 7 hours postdose as able (ePRO).
The following endpoint will be assessed across the entirety of the study.

Status of subject’s antidrug antibody (ADA) assessment (ie, ADA-negative or ADA positive, and low or high 
ADA titer).
Statistical Considerations:
This is a repeated crossover design and all analysis will adjust for treatment and sequence. For summarizations on or 
prior to randomization tables will be summarized by sequence. For safety and efficacy summarizations after 
randomization, tables will be summarized by Treatment and administration of treatment (ie first and second). More 
complex analysis are described below and further detailed in the statistical analysis plan (SAP).
Analysis Sets
The full analysis set (FAS) will include all subjects who were randomized and received at least 1 dose of study 
medication. 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. Subjects who were randomized 
without any CVS episode within the first 10 weeks and were replaced will be excluded from the efficacy analysis.
The per protocol analysis set (PPS) 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 PPS will 
be made before the unblinding of the study. Analyses using the PPS will be provided as a sensitivity analysis.
The safety analysis set will include all subjects who were randomized and received at least 1 dose of study medication. 
Subjects will be analyzed according to the treatment they actually received. 
The PK set will consist of all subjects who receive at least 1 dose of study medication and have at least 1 measurable 
plasma concentration.
The immunogenicity set consists of subjects who receive at least 1 dose of study medication and have ADA status 
assessment at baseline, and at least 1 postbaseline sample.
Safety Analysis
Safety data will be summarized by treatment groups using the safety analysis set. No formal statistical testing or 
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Study ID TAK-951-1501
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CONFIDENTIAL
inference will be made.
AEs will be coded using the Medical Dictionary for Regulatory Activities, Version 23.0 or higher and will be 
summarized by System Organ Class and Preferred Term by treatment groups. Absolute values and changes from 
baseline in clinical safety laboratory tests, vital signs, and ECG parameters will be summarized descriptively for each 
treatment group. Values outside normal ranges and potentially clinically significant values will be flagged and 
tabulated.
Efficacy Analysis
Efficacy analyses will be conducted using the FAS. Sensitivity analyses based on the PPS will be performed for 
selected secondary efficacy endpoints (data collected via ePRO and eObsRO devices). Nominal p-values will be 
presented when appropriate. All efficacy data within the first 30 minutes immediately following TAK- 951/placebo 
administration will be excluded from the efficacy analysis to allow for inclusion of those subjects who are dosed after 
the onset of the emetic phase. Clinical laboratory data will be summarized by treatment and administration using the 
following: n, mean, median, standard deviation, minimum and maximum observed values. Post-baseline assessments 
will also contain average change from the baseline values. Vital signs will include HR (bpm), respiratory rate, systolic 
and diastolic blood pressure which will be summarized descriptively by treatment and administration.
Secondary Efficacy Endpoints
Binary secondary efficacy endpoints (total response, absence of emesis, absence of nausea and no need for rescue 
medication at 2, 4, and 8 hours postdose). These endpoints will be summarized by treatment groups as observed. 
Treatment difference between TAK-951 and placebo will be estimated and the associated 95% CI will be constructed 
using normal approximation. Binary efficacy endpoints will be analyzed using a nonlinear mixed effects model 
(NLMEM) with repeated measures with treatment, sequence, period, treatment-by-timepoint interaction, and 
treatment-by-timepoint-by-period interaction as fixed effects and subject-within-sequence as a random effect based on 
the observed data as the main analysis method. The odds ratio between TAK-951 and placebo, the associated 95% CI, 
and nominal p-value obtained from the nonlinear mixed effects model will be presented. Binary efficacy endpoints 
may also be analyzed using generalized linear mixed effects model with fixed effects of sequence, treatment and 
period with random effect of subject modeled with a no diagonal factor analytic (FA0(2)) covariance structure with 
residual covariance matrix modeled by variance component grouped by treatment. Model based estimates comparing 
treatments along with corresponding CI in case the NLMEM model does not fit.
Longitudinal continuous secondary endpoints (peak nausea VRS at 0, 1, 2, 4, and 8 hours postdose and change in 
nausea VRS at 1, 2, 4, and 8 hours postdose [on a verbal response scale]), will be analyzed using a mixed model for 
repeated measures (MMRM) as observed. This MMRM model will include treatment, sequence, period, timepoint, 
treatment-by-timepoint interaction, and treatment-by-timepoint-by-period interaction as fixed effects, and 
subject-within-sequence as a random effect. Point estimates, the associated 95% CIs, and nominal p-values for 
treatment difference between TAK-951 and placebo by timepoint will be presented.
Missing data by patient and observer may be examined at each timepoint as well as by treatment assignment.
Exploratory Efficacy Endpoints
The exploratory endpoint assessments will be summarized descriptively by treatment groups as observed. Descriptive 
statistics for continuous endpoints will include number of subjects, number of observations, mean, standard deviation, 
median, minimum, and maximum. Descriptive statistics for binary or categorical endpoints will include count and 
percentage. The time-to-event endpoints will be summarized by treatment groups. Subjects without documented 
events will be censored. Kaplan-Meier estimates and plots will be provided.
PK Analysis
No formal noncompartmental PK analysis will be performed on concentration-time data. Summary statistics of 
plasma concentrations will be summarized using the PK set. Individual concentration data will be included in the 
listings using the PK set. A population PK analysis may be conducted, and a more detailed description of these 
analyses may be given in a separate analysis plan. The results of these analyses will not be included in the clinical 
study report and may be a standalone report, if needed.
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Study ID TAK-951-1501
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CONFIDENTIAL
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, and low or high ADA titer.
ADA Negative – defined as subjects who do not have a confirmed positive ADA status in any postbaseline 
assessment.
ADA positive – defined as subjects who have confirmed positive ADA status in any postbaseline assessment.
High ADA titer – defined as subjects who have at least 1 postbaseline ADA titer greater than a cutoff to be determined 
based on the actual titer data.
Low ADA titer – defined as subjects whose postbaseline ADA titer numbers are all less than or equal to a cutoff to be 
determined based on the actual titer data.
ADA status and titer will be listed by subjects.
For effect of ADA on efficacy, subjects may be summarized within each ADA response status (negative, positive, 
high and low titer).
For effect of ADA on safety, subjects’ incidence of AEs by ADA response status (negative, positive, high and low 
titer) may be provided. Injection-site reactions (preferred term) may also be summarized by ADA status. The same 
analysis may be repeated based on ADA titer.
The relationship between immunogenicity status (ADA and ADA titer) and PK may be explored.
Sample Size Justification: 
A total sample size of ~20 subjects is considered sufficient for evaluation of safety and tolerability of intermittent 
single SC doses of TAK-951 in subjects with moderate to severe CVS during the prodromal/early emetic phase at 
home. The study is not statistically powered to perform any hypothesis testing in the study.
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Study ID TAK-951-1501
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Protocol Incorporating Amendment No. 1
19 November 2021
CONFIDENTIAL
1.1
Protocol Amendment 1 Summary of Changes
Protocol Amendment 1 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are:

Minor wording, editorial, formatting and grammatical changes to improve clarity.

Increased number of sites to accommodate revised recruitment rate estimates.

To modify study sequences (ie, from 4 to 2 randomized sequences with the same 
2-treatment repeated crossover design) to improve anticipated study retention rates to 
reduce impact of missing data for early discontinuation.

To address Food and Drug Administration (FDA) comments regarding definitions of 
sterility and contraceptive duration.

To remove efficacy timepoints at 12 and 24 hours from the protocol.
In this amendment, minor grammatical, editorial, formatting, style 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
Change
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Section 1.0 STUDY 
SUMMARY
Planned number of sites changed 
from 4 to 10.
Further evaluation of the recruitment 
rate and site feedback led to revised 
estimates for the number of sites 
needed.
2.
Section 1.0 STUDY 
SUMMARY
Section 1.0 STUDY 
SUMMARY
Changed ‘6 months’ to 30 days’ for 
contraception requirement postdose, 
added postmenopausal 
follicle-stimulating hormone criteria 
in Inclusion Criterion # 10 
Modified for consistency across 
informed consent form (ICF) and 
protocol as per Food and Drug 
Administration (FDA) comments.
3. 
Section 1.0 STUDY 
SUMMARY
Section 7.2 Exclusion 
Criteria
Clarified prohibition of 
prochlorperazine or promethazine as 
a rescue medication until >30 hours 
(5 half-lives of TAK-951) after IP 
administration.
Combinatorial cardiovascular risk is 
anticipated to be minimal after 5 
half-lives of TAK-951.
4.
Section 1.0 STUDY 
SUMMARY
Added to Efficacy Analysis “Clinical 
laboratory data will be summarized 
by treatment and administration 
using the following: n, mean, 
median, standard deviation, 
minimum and maximum observed 
values.”
Clarification of analysis plan for 
clinical laboratory data. 
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Study ID TAK-951-1501
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CONFIDENTIAL
Protocol Amendment 1
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 
Schematic
Simplified study sequences from 4 to 
2. 
Replaced Figure 2.a. with an updated 
figure. 
Simplification of the study design to 
a 2-sequence, 4-period, 2-treatment 
repeated crossover design to reduce 
the drop out risk from certain 
sequences in original design.
6.
Section 3.0 Schedule of 
Study Procedures
Addition of twice monthly site calls 
to subject as mechanism to collect 
interepisode adverse events (AEs) 
and healthcare encounters.
Supports subject safety and enhances 
AE data collection. Healthcare 
encounters eCRF has been added to 
collect information relating to 
hospitalizations and/or outpatient 
clinic visits.
7.
Section 5.2 Endpoints
Section 1.0 STUDY 
SUMMARY
Section 12.0
STATISTICAL Methods
Removed 12- and 24-hour efficacy 
timepoints throughout.
Revised electronic clinical outcome 
assessments and removed the 12- and 
24-hour timepoints based on 
recommendations of experts in cyclic
vomiting syndrome (CVS). 
8.
Section 6.1 Study Design
Changed last 6 lines of the fourth 
paragraph to “No episodes will be 
eligible for dosing in the study until 
>14 days after randomization. A 14 
day washout begins immediately 
following study drug/placebo dosing. 
Subjects who meet stopping criteria
will be discontinued from the study 
and may be replaced by another 
subject. Subjects who do not have a 
CVS episode within 10 weeks of 
randomization or their last dosed 
CVS episode and subjects who 
withdraw may be replaced in order 
for approximately 20 subjects to 
complete the study”.
Expansion of washout period 
between doses from 7 to 14 days to 
provide additional buffer between 
CVS episodes. 
Clarification of rules for subject 
replacement.
9.
Section 6.1 Study Design
Added to the fourth paragraph: “The 
randomization sequencing will not 
advance if the subject is not dosed for 
a CVS episode (eg, if the subject is 
scheduled to receive placebo during 
that episode and is not dosed, they 
will still be scheduled to receive 
placebo as per the randomization 
sequence for the next episode that is 
eligible for dosing).” “For 
spontaneously aborted episodes (eg, 
‘false’ prodromes where symptoms 
Clarifies scenarios in which sequence 
randomization should not advance. 
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CONFIDENTIAL
Protocol Amendment 1
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
have resolved and the subject no 
longer believes that they are having 
an impending CVS emetic episode 
by the time the HCP arrives), the 
subject may decline dosing and the 
randomization sequence will not 
advance.”
10.
Section 9.1.1.1
Assignment of Screening 
and Randomization 
Numbers
Added “Sponsor or sponsor delegate 
approval is required for rescreening 
subjects,” to the end of the first 
paragraph.
Addition to assure sponsor oversight 
of rescreening.
11.
Section 9.3.2 Chemistry
Added “Estimated Creatinine 
Clearance” to chemistry evaluations 
table.
Addition to support renal exclusion 
criteria 
.
12.
Section 9.4 PK, 
Immunogenicity, and 
DNA Samples
Added a row in the specimen table 
for whole blood sample for DNA.
Additional optional collection of 
whole blood for DNA sequencing to 
allow data bridging as the biomarker 
program moves to this preferred 
method of collection for improved 
sequencing accuracy.
13.
Section 9.5.5 Pregnancy
Removed “5 half-lives or” from first
paragraph
Harmonizing language across 
documents (protocol and ICF) 
 
14.
Section 10.2.8.2
Reporting AEs
Added “All hospitalizations, 
including those deemed to be related 
to CVS but not TAK-951/placebo as 
well as reasons for admission (ie, 
intractable nausea/vomiting due to 
CVS, tachycardia, hypotension etc), 
should be reported to the sponsor 
however AEs related to the 
underlying study disease (CVS) will 
not be reported as AEs unless they 
are deemed to be treatment-related 
SAEs” to end of first paragraph.
Clarification.
Property of Ta
o Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CONFIDENTIAL
Protocol Amendment 1
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.
Section 10.2.8.4
Management of Specific 
AEs
Removed “In addition, an LFT 
Increases eCRF must be completed 
and transmitted with the Takeda SAE 
form (as per Section 10.2.9).” from 
last paragraph under Abnormal 
LFTs.
Clarification: abnormal liver function 
test (LFT) results meeting a Hy’s 
Law event (eg, alanine 
aminotransferase or aspartate 
aminotransferase >3× upper limit of 
normal (ULN) and total bilirubin >2× 
ULN for which an alternative 
etiology has not been identified) will 
be reported as part of SAE 
documentation rather than in LFT 
increase electronic case report form.
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Study ID TAK-951-1501
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Protocol 
19 November 2021
CONFIDENTIAL
2.0
STUDY SCHEMATIC
Figure 2.a
Study Schematic
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Protocol 
19 November 2021
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Screening
Random 
ization
Day ≥-14 a Prodrome 
Episodes 1 - 4
End of 
treatment/
end of study
visit d
Scheduled Time (in hours)b
Pre-
dose
0 0.25 0.5 0.75
1
1.25 1.5 1.75 2
2.5
3
3.5 4 4.5
5
6
7
8
24
Wash-
out 
Period c Inter-ep
isode
Procedures/ Assessments
Informed consent
X
Inclusion/exclusion criteria
X
Medical history/demographics
X
Prior/concomitant medication review
X
X
X
Medication storage/
procedure review
X
Physical examination e
X
X
X
BMI
X
Remote home screening a
X
Randomization f
X
HCP contacted
X g
HCP arrives
X h
HCP departs
X
TAK-951/placebo administration
Xi
Rescue medication 
self-administration j
X
Safety Assessments
AE monitoring k
X-----------------------------------------------------------------------------------Continuous Monitoring----------------------------------------------------------------X
Semirecumbent HR/BP l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X X
X
X
Standing HR/BP m
X
X
X
X
X
12-lead ECG n
X
X
Temperature o
X
X
X
Continuous single lead ECG (patch)
X-----------------------Continuous Monitoring--------------------X
HR (patch)
X-----------------------Continuous Monitoring--------------------X
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Study ID TAK-951-1501
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Protocol 
19 November 2021
CONFIDENTIAL
Screening
Random 
ization
Day ≥-14 a Prodrome 
Episodes 1 - 4
End of 
treatment/
end of study
visit d
Scheduled Time (in hours)b
Pre-
dose
0 0.25 0.5 0.75
1
1.25 1.5 1.75 2
2.5
3
3.5 4 4.5
5
6
7
8
24
Wash-
out 
Period c Inter-ep
isode
Interepisode telephone contact p
X
Clinical Outcome Assessments
ePRO q
X
X
X
X
X
X
X X X
X
X
X
eObsRO q
X
X
X
X
X
X
X X X
X
Post episode interview r
X
Event marker
X-----------------------Continuous Monitoring--------------------X
X-----------------------Continuous Monitoring--------------------X
Audio data recording s
X-----------------------Continuous Monitoring--------------------X
Laboratory Procedures/Assessments
Safety laboratory collection 
(hematology and serum chemistry)
X
X
Urinalysis
X
X
Urine drug screen
X
Alcohol breath test
X
Hepatitis screen t
X
HIV screen
X
Beta-hCG (pregnancy) test u
X
Urine pregnancy test v
X
Serum FSH test v
X
Blood glucose level (finger stick)
X
PK Assessments
Plasma sample for TAK-951 PK 
(venipuncture)
X
X w
X
Immunogenicity and Biomarker 
Evaluations
Serum sample for immunogenicity
X
X
Buccal epithelial cell sample for DNA 
(optional)y
X
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3.5 4 4.5
4
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TAK-951
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Page 21 of 93
Protocol 
19 November 2021
CONFIDENTIAL
Screening
Random 
ization
Day ≥-14 a Prodrome 
Episodes 1 - 4
End of 
treatment/
end of study
visit d
Scheduled Time (in hours)b
Pre-
dose
0 0.25 0.5 0.75
1
1.25 1.5 1.75 2
2.5
3
3.5 4 4.5
5
6
7
8
24
Wash-
out 
Period c Inter-ep
isode
Blood sample for DNA (optional) y
X
X-----------------------Continuous Monitoring--------------------X
Other
Supine/semirecumbent position z
X----------Continuous Monitoring-------------------X
Location
Site
Subject’s home
Site
AE: adverse event; anti-HCV: antibodies to hepatitis C virus; beta-hCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; bpm: beats per minute; CVS: cyclic 
vomiting syndrome; ECG: electrocardiogram; eCRF: electronic case report form; eObsRO: electronic observer-reported outcomes; ePRO: electronic patient reported outcome; ET: early 
termination; FSH: follicle-stimulating hormone; HBsAg: hepatitis B surface antigen; HCP: healthcare professional; HR: heart rate; PK: pharmacokinetic.
a Home screening to assess the subject's home will take place before randomization. The home screening does not have to occur on the same day as physical screening but randomization may not 
occur until both physical and home screening are complete and the subject is eligible.
b All scheduled measurements may occur within ±5 minutes of the scheduled episode timepoints until the 4-hour timepoint, and within ±10 minutes for all subsequent episode timepoints.
c The 14 day washout begins immediately following study drug/placebo dosing.
d Visit should occur between 7 to 10 days after the last dose or when the subject is terminated from the study.
e Physical examination at the indicated visit will be symptom driven.
f Subjects will be randomized to study treatment after the screening visit is complete. No episodes will be eligible for dosing in the study until >14 days after randomization.
g At the initiation of the prodrome, the subject will contact a study HCP who will arrive at the subject’s home as rapidly as possible.
h On arrival, the HCP will complete initial vital signs, initiate the remote wearable patch and event marker, and activate the audio data recorder.
i TAK-951/placebo administration by the HCP will occur in the specified window and no later than 1 hour after the onset of the emetic phase. Postdose monitoring will occur relative to when the 
dose was administered within the administration window.
j Should the subject experience continued, persistent, stereotypic emesis >2 hour postdose, rescue medication will be allowed for self-administration.
k Collection of AEs will commence at the time the subject signs informed consent. A Healthcare Encounters eCRF will be utilized as part of the AE collection. 
l All BP and pulse assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The HCP can take a third measurement if there is 
inconsistency between assessments. The final recorded number should be the averaged and decimals should be rounded up to whole numbers based on standard rounding rules. For pre-dose 
HR/BP assessments, all 3 potential measurements should be obtained within 5-25 minutes of each other in total, with the final set occurring immediately before dosing.
m For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still for 
approximately 3 minutes before this assessment.Standing assessments must not be performed if semirecumbent systolic BP is <85 mm Hg, or if the subject presents with signs or symptoms 
suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision). Orthostatic BP/HR assessments may occur earlier than 2 hours postdose if supported
by ongoing review of safety data as detailed in Section 6.1.
n 12-lead ECG will occur as shown and ad hoc per protocol during HCP monitoring period.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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19 November 2021
CONFIDENTIAL
o Temperature measurements to be completed as able.
p Site will contact subject by phone/televisit to collect any inter-episode AEs and Healthcare encounters every 14d ±4d.
q Refer to TAK-951-1501 Clinical Outcome Assessment Scales and Questionnaires.
r Timing of interview to be determined based on subject’s report of episode resolution via ePRO. There are up to 2 interviews: 1) embedded interview, which takes place after the end of 1st 
episode for the first 5 voluntary patients and their associated HCPs, 2) study exit interview, which takes place after study completion for up to all 20 subjects (participation is on voluntary basis).
s Continuous audio data recording will be initiated by the HCP upon arrival at the subject’s home and will be discontinued at the HCP’s departure.
t Hepatitis panel, including HBsAg and anti-HCV.
u Serum/urine pregnancy test for female subjects of childbearing potential only.
v Serum FSH level will be obtained for postmenopausal women. A high FSH level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in younger 
women (eg, those aged <45 years) or women who are not using hormonal contraception or hormonal replacement therapy.
w PK sample will be collected ±1 hour of the scheduled PK timepoint. The actual time of sample collection must be recorded.
x Dosed subjects only.
y Buccal swabs and whole blood collection for the DNA sample can be collected at any time on the day of the end-of-treatment/end-of-study visit for those subjects that consent to the optional 
DNA sample collection. Both buccal swabs and whole blood are to be collected from each of the consenting subjects.
z Subjects are required to remain supine/semirecumbent for ~2 hours following study drug administration, however the subject may be mobilized at 2 hours or earlier following study drug 
administration if desired and asymptomatic as defined in Section 6.1.
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TAK-951
Study ID TAK-951-1501
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CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
Cyclic vomiting syndrome (CVS) is a chronic, disabling, functional disorder of unknown etiology
for which there are no approved treatments to date for adults or children. The disease course is 
characterized by recurrent, stereotypical episodes of primarily incapacitating nausea and vomiting 
lasting hours to days, interspersed with varying lengths of symptom-free intervals between emetic
episodes. During the prodromal and emetic phases, many symptoms other than nausea are often 
experienced by patients including headache, abdominal pain and sweating.
CVS is characterized by 4 phases; the inter-episode phase when patients are at their baseline health 
between episodes; the prodromal phase lasting on average 55 minute (window), where the patient
senses an approach of an episode and can experience a variety of symptoms including: panic, 
lethargy, pallor, anorexia, and nausea of varying intensity; the emetic phase characterized by 
repeated, unrelenting nausea, vomiting, retching, and abdominal pain lasting hours to days; and the 
recovery phase with resolution of nausea and vomiting and return of energy, strength and appetite. 
Many CVS patients occasionally require emergency services for supportive care during severe 
episodes and may even require hospitalization for symptom management.
On average, patients with CVS experience 6 to 12 cycles per year. CVS affects both children and 
adults: 1) in children, estimated prevalence is approximately 0.05% to 1.9%, with median age of 
onset 5 to 6 years old; 2) in adults, estimated prevalence is approximately 1% to 2%, with mean 
age of onset 22 to 35 years old [1,2]. Migraine, autonomic instability, and psychological
conditions (such as anxiety and depression) are common comorbidities.
Diagnosis of CVS is based on the Rome IV criteria (adults and children) and the North American 
Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria (pediatric only) and 
must include stereotypic episodes of vomiting over the preceding 6 months with intervening 
periods of wellness [3,4]. Recent guidelines also discriminate between mild disease 
(<4 episodes/year) and moderate to severe (≥4 episodes/year) [5]. CVS is associated with greater 
impairment of health status and worse quality of life than other functional gastrointestinal 
disorders.
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Study ID TAK-951-1501
Page 24 of 93
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CONFIDENTIAL
4.2
Rationale for the Proposed Study
Unmet need in moderate to severe CVS is high due to the lack of regulatory approved therapies, 
poor or unknown efficacy of off-label agents, and unrelenting CVS episodes that result in costly 
emergency room (ER) visits/hospitalizations. For prodrome or emetic phases, off-label abortive 
options typically administered at home include: 1) antiemetics (eg, ondansetron, aprepitant), 
2) triptans for those patients with clear migraine overlay, and 3) anxiolytics (benzodiazepines). If 
these efforts fail and the patient requires ER management, 1) intravenous antiemetics, 2) sedatives 
(eg, benzodiazepines, antihistamines) if treatment failure with antiemetics, and 3) supportive care 
including intravenous fluids and pain control to diminish patient discomfort until the episode 
self-resolves are provided. While multiple classes of medications are recommended off-label by
guidelines for abortive treatment, evidence of efficacy is limited to uncontrolled retrospective 
studies and case series. The lack of data from prospective, placebo-controlled studies and the fact 
that all of these treatments are used off-label due to lack of approved treatment results in a high 
unmet medical need for approved treatments. 
For CVS prophylaxis, which is typically prescribed to patients with moderate to severe CVS, 
off-label prophylactic options include antihistamines, tricyclic anti-depressants, anti-epileptics, 
anti-psychotics, selective natural killer 1 receptor antagonists, β-blockers, vitamins and 
supplements. CVS prophylaxis may be avoided as the current options have significant side effects, 
a key issue for a chronic reoccurring condition. 
The safety, tolerability and pharmacokinetics (PK) of single TAK-951 doses 
 
subcutaneous (SC) was evaluated in healthy volunteers in the first-in-human (FIH) Study
(TAK- 951-1001) 
.
TAK-951 is proposed for the treatment of conditions associated with nausea and vomiting and is 
currently being investigated in PONV. Based on data from the completed FIH study 
TAK-951-1001, nonclinical findings from studies conducted with TAK-951,
 and the known mechanism of action of GIP postural hypotension is an identified risk and 
potential risks include heart rate (HR) increase, hypotension, hypersensitivity, injection site 
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TAK-951
Study ID TAK-951-1501
Page 25 of 93
Protocol 
19 November 2021
CONFIDENTIAL
reactions, immunogenicity, synergistic effect when combined with beta-blockers, and effects on 
lipid metabolism and bone resorption.
TAK-951 is being developed as a potential first line, fast-acting therapy to abort the impending 
emetic episode if taken during the prodromal phase or terminate the episode if taken in the early
emetic phase, in the at-home setting. Further understanding of the cardiovascular effects 
 along with efficacy results from ongoing TAK-951 clinical 
studies will inform the appropriateness of use of this fast-acting agent in aborting CVS prodrome 
or emesis at home.
4.3
Benefit/Risk Profile
The main purpose of this is to evaluate the safety and tolerability of intermittent single doses of 
TAK-951 in the abortive treatment of subjects with CVS.
As published studies have described increased HR and decreased blood pressure (BP) 
and a proposed mechanism of vasodilation (refer to investigator’s brochure), it is 
hypothesized that TAK-951 causes vasodilation, which leads to decreased BP, tachycardia and 
orthostatic findings in some individuals.
Based on the safety findings from nonclinical studies conducted with TAK-951, increased HR, 
decreased BP, and synergistic effect when combined with beta blockers are potential risks. Safety
results from the FIH study indicated a trend of increase in HR and decrease in diastolic BP 
observed in TAK-951 groups. No observed trend in systolic blood pressure was noted. 
Additionally, orthostatic changes in HR and BP were observed in some individuals in the 
TAK-951 group. Orthostatic hypotension is considered an identified risk. After receiving 
TAK-951 in Part 1 or Part 3 of Study TAK-951-1001, 5 subjects experienced orthostatic 
hypotension, including 1 subject with a Grade 3 event and 2 subjects with Grade 2 events. Postural 
dizziness was reported by 7 subjects. For peptide-based therapeutics administered SC, 
immunogenicity and injection site reactions and more serious hypersensitivity reactions are 
always possible; no events were reported in Part 1, 2 subjects reported injection site pain and 1 
subject reported injection site induration in Part 3.
Safety will be assessed by monitoring for adverse events (AEs), vital signs (pulse, and both 
semirecumbent and standing BP [after 2 hours as tolerated]), remote continuous single-lead 
electrocardiogram (ECG), safety laboratory assessments (serum chemistry, hematology, 
urinalysis), and immunogenicity.
The following risk mitigation plan will be employed:
!
Exclusion of subjects with cardiovascular conditions and cardiovascular history as 
specified in Section 7.2.
!
Exclusion of subjects with a history of frequent dehydration due to CVS episodes requiring 
ER or intravenous fluid management as specified in Section 7.2.
!
Exclusion of subjects who do not meet vital sign criteria immediately before each dose as 
specified in Section 7.2.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-951
Study ID TAK-951-1501
Page 26 of 93
Protocol 
19 November 2021
CONFIDENTIAL

Well defined stopping criteria in the study to manage the cardiovascular risk related to 
TAK-951 as specified in Section 6.4.4.

Exclusion of medications with known hypotensive side effects.

Inclusion in the investigator's brochure of detailed guidance to investigators for 
management of potential HR and BP effects (including understanding of the potential 
underlying vasodilatory actions of TAK-951).

Crossover study design to reduce the total number of subjects needed.

Healthcare professional (HCP), such as registered nurse or nurse practitioner, monitoring 
in the home setting including vital signs, placing intravenous lines and administering 
intravenous fluids as indicated, drawing samples for clinical laboratory assessment, and 
interpreting digital rhythm strips as necessary.

HCP administration of the study drug/placebo in the supine/semirecumbent position with 
subsequent observation and monitoring in that position following administration to 
mitigate the risk of orthostatic hypotension and other cardiovascular AEs with additional 
continued monitoring for 8 hours postdose.
An external Data Monitoring Committee (DMC) will be used 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. The sponsor may pause or stop enrollment at any 
time. Study drug dosing may resume if no safety concern is identified.
Overall, the proposed risk mitigation plan is adequate to monitor subjects enrolled in the study.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Study Objectives
5.1.1
Study Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of intermittent single 
SC doses of TAK-951 in subjects with CVS during the prodromal/early emetic phase at home.
5.1.2
Study Secondary Objective
The secondary objective(s) of the study are:

To evaluate the efficacy of intermittent single SC doses of TAK-951 in subjects with CVS.

To assess the immunogenicity after intermittent single SC doses of TAK-951 in subjects 
with CVS.
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TAK-951
Study ID TAK-951-1501
Page 27 of 93
Protocol 
19 November 2021
CONFIDENTIAL
5.1.3
Study Exploratory Objectives
Exploratory endpoints of this study include: 

To evaluate the PK of TAK-951 following intermittent single SC doses in subjects with 
CVS.

To evaluate additional efficacy parameters of intermittent single SC doses of TAK-951 in 
subjects with CVS.
5.2
Endpoints
5.2.1
Primary Endpoint
5.2.2
The primary endpoint is the assessment of vital signs, laboratory values, and AEs.
Secondary Endpoints 
The secondary endpoints exclude the first 30 minutes immediately following TAK-951/placebo 
administration. 
The following endpoints will be assessed within 2, 4, and 8 hours postdose: 

Total response (Yes/No), defined as no emesis, no nausea (verbal rating scale [VRS] “none”) 
and no need for rescue therapy before each timepoint (by both electronic reported 
patient-outcomes [ePRO] and electronic observer-reported outcomes [eObsRO] inclusive). 

Absence of emesis (Yes/No), defined as no emesis and no need for rescue medication before 
each timepoint (by both ePRO and eObsRO, inclusive).

Absence of significant nausea (Yes/No), defined as VRS of “none” or “mild” and no need for 
rescue medication before the evaluation timepoint (ePRO).

Peak nausea VRS score at 0, 1, 2 hours in all subjects and 4, 8 hours postdose without receiving 
rescue medication before the evaluation timepoint (ePRO). Data will also be collected at 3, 5, 
6, and 7 hours postdose as able.

Change in nausea VRS score at 1 and 2 hours in all subjects and 4, 8 hours postdose as 
compared with predose score without receiving rescue medication before the evaluation 
timepoint. Data will also be collected at 3, 5, 6, and 7 hours postdose as able (ePRO).
The following endpoint will be assessed across the entirety of the study.

Status of subject’s antidrug antibody (ADA) assessment (ie, ADA-negative or ADA-positive, 
and low or high ADA titer).
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TAK-951
Study ID TAK-951-1501
Page 28 of 93
Protocol 
19 November 2021
CONFIDENTIAL
5.2.3
Exploratory Endpoints
All exploratory endpoints exclude the first 30 minutes immediately following TAK-951/placebo 
administration.
Exploratory endpoints will be assessed through the following parameters: 
1. Efficacy
–
Number of emeses by hour (eg, 0-1h, 1-2h, 2-3h, etc) (ePRO, eObsRO, event marker, 
audio recording).
–
Absence of emesis within 2 hours postdose (Yes/No) (event marker, audio recording).
–
Absence of emesis within 4 hours postdose (Yes/No) in subjects who have not received 
rescue medication before the evaluation timepoint (event marker, audio recording).
–
Absence of emesis within 8 hours postdose (Yes/No) in subjects who have not received 
rescue medication before the evaluation timepoint (event marker, audio recording).
–
Time from dose to first emetic event (vomiting or retching), within each episode—(ePRO, 
eObsRO, event marker, audio recording).
–
Total duration (min) of CVS episode, defined as time from study dose to 
subject-determined resolution of episode (ie, back to baseline status) (ePRO).
–
Abdominal pain (peak score) at 0, 1, and 2 hours in all subjects and 4, and 8 hours postdose 
in subjects who have not received rescue medication before the evaluation timepoint 
(ePRO). Data will also be collected at 3, 5, 6, and 7 hours postdose as able.
–
Headache (peak score) at 0, 1, 2 hours in all subjects and 4, and 8 hours postdose in 
subjects who have not received rescue medication before the evaluation timepoint (ePRO). 
Data will also be collected at 3, 5, 6, and 7 hours postdose as able.
–
Health-related quality of life (HRQOL) PROMIS-29 at baseline and in inter-episodic 
phase every 4 weeks (ePRO).
–
Number of emergency department visits for CVS per CVS episode (Yes/No) (as defined by 
onset of prodrome in 1 study episode to subject’s definition of resolution of that episode) 
(ePRO, electronic case report form [eCRF]).
–
Number of hospitalizations for CVS per CVS episode (as defined by onset of prodrome in 
1 study episode to subject’s definition of resolution of that episode) (ePRO, eCRF).
–
Rescue medication usage per CVS episode (as defined by onset of prodrome in 1 study 
episode to subject’s definition of resolution of that episode) (Yes/No) (ePRO, eObsRO).
–
Time from dosing to first use of rescue medication within each CVS episode (as defined by 
onset of prodrome in 1 study episode to subject’s definition of resolution of that episode) 
(ePRO, eObsRO).
–
Missed days of school/work due to CVS per CVS episode (as defined by onset of prodrome 
in 1 study episode to subject’s definition of resolution of that episode) (ePRO).
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TAK-951
Study ID TAK-951-1501
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Protocol 
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CONFIDENTIAL
–
Usability and feasibility of ePRO, eObsRO and audio monitor recording (embedded 
interviews after the 1st episode with patients and HCP and study interviews after the 
completion of this study with patients). Participation to interviews are all on voluntary
basis.
–
Subject activity as a proxy for functional disability 
).
–
Change 
 from baseline (predose) to first emesis in those 
subjects who receive prodromal dosing (wearable event marker).
2. Individual plasma concentrations for TAK-951.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, double-blind, repeat crossover placebo-controlled study to evaluate the 
safety, tolerability, efficacy, PK, and feasibility of episodic administration at home of
TAK- 951/placebo in subjects aged 18 to 50 years, inclusive, during the prodromal and early
emetic phase in subjects with moderate to severe CVS. Approximately 20 subjects will be 
randomized to treatment sequence in this study.
Consented subjects will be screened for eligibility before randomization. Of note, data from Study 
TAK-951-1001 FIH study showed that 34% of healthy volunteers experienced orthostatic 
tachycardia (<5% symptomatic) as defined as >120 beats per minute (bmp) or an increase in HR 
upon standing of >30 bpm, and approximately 13% experienced orthostatic hypotension (<5% 
symptomatic) defined as a decrease upon standing of >20 mm Hg systolic, 10 mm Hg diastolic, or 
both at any time point after dosing with effects lasting approximately 2 to 4 hours. It is 
hypothesized that TAK-951 causes vasodilation that leads to these observed hemodynamic 
changes. At the screening visit, baseline physical examination, medical history including 
cardiovascular history and any history of autonomic dysfunction, safety laboratory tests, ECG, 
vital signs, orthostatic BP and HR will be assessed. Given that CVS may also be associated with 
comorbidities involving autonomic dysfunction, subjects will be screened to exclude baseline 
orthostatic hypotension and postural tachycardia as part of their cardiovascular history and vital
sign assessments. Before randomization, the at-home setting will be evaluated for proximity to a 
visiting home health provider, potential drug storage conditions will be assessed for study 
feasibility, and safety. The home screening does not have to occur same day as physical screening 
but randomization may not occur until both physical and home screening are complete and the 
subject is eligible. Those subjects who are eligible will then be randomized into the study. 
Randomized subjects will use a variety of devices to facilitate their participation in this 
decentralized study including: tablet or hand-held mobile device for ePRO diary, wearable patch 
and accompanying bedside monitor tablet, wrist-worn event marker, audio recording device, BP 
cuff, and glucometer, as well as a small temperature-monitored freezer for drug/placebo home 
storage. 
The at-home portions of the study will be supported by home HCPs (registered nurse, nurse 
practitioner, etc.) who will have a skill set including but not limited to the ability to: monitor vital 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-951
Study ID TAK-951-1501
Page 30 of 93
Protocol 
19 November 2021
CONFIDENTIAL
signs, draw/prepare samples for clinical laboratory assessment, place an intravenous line if 
necessary, administer intravenous fluids if indicated, and review a digital rhythm strip if indicated.
Approximately 20 subjects will be randomized to treatment sequence in 1 of 2 groups with 
10 subjects per group as outlined in Figure 2.a. In this 4 episode, 52-week randomized, 
double-blind, repeat crossover, placebo-controlled study to evaluate the safety, tolerability, 
efficacy, PK, and feasibility of episodic administration at home of TAK-951/placebo. Subjects 
will receive a single dose of TAK 951 or placebo at each of the 4 anticipated CVS episodes over a 
maximum 52-week study period in a double-blind manner (subject, sponsor and investigator 
blinded). No episodes will be eligible for dosing in the study until >14 days after randomization. A 
14 day washout period begins immediately following study drug/placebo dosing. Subjects who 
meet stopping criteria will be discontinued from the study and may be replaced by another subject. 
Subjects who do not have a CVS episode within 10 weeks of randomization or their last dosed 
CVS episode and subjects who withdraw may be replaced in order for approximately 20 subjects 
to complete the study. 
At the initiation of the prodrome (ie, first recognition by the subject of 1 or more of their usual 
symptoms of CVS prodrome) in each of the assessed CVS episodes, the subject will immediately 
contact the home health provider company, produce a urine sample if necessary, and remove the 
blinded dose from the freezer to thaw at room temperature. Temperature excursion data supports 
dose stability up to 4 hours and dose thaw within 20 minutes at room temperature. 
The HCP will arrive at the subject’s home as rapidly as possible following contact from the subject 
to allow for dosing no later than 1 hour after onset of the emetic phase. The HCP will complete 
predose checks as outlined in the Schedule of Study Procedures (Section 3.0), initiate the wearable 
patch and wrist-worn wearable device (event marker). Additionally, the HCP will activate a 
passive recording device for exploratory audio data collection of retching and emesis during the 
study period. The double-blind study drug/placebo will be administered to eligible subjects based 
on predose vital signs during the continued prodrome or no later than 1 hour after the onset of the 
emetic phase. Immediately before dosing in each CVS episode, any subjects who meet any 
cardiovascular criteria detailed below upon vital sign assessment during the Predose time period, 
the planned dose will not be administered during that episode. The randomization sequencing will 
not advance if the subject is not dosed for a CVS episode (eg, if the subject is scheduled to receive 
placebo during that episode and is not dosed, they will still be scheduled to receive placebo as per 
the randomization sequence for the next episode that is eligible for dosing). Subjects will not be 
dosed during that episode if one or more of the following is found: subjects who have a SBP of ≤90 
or ≥150 or a diastolic (DBP) <60 or >95 mm Hg, or HR ≤50 or ≥110 bpm. Athletic subjects with a 
HR <55 bpm may be enrolled based upon the investigator’s judgement provided that HR is >45 
bpm and rhythm is sinus bradycardia at screening but are required to meet the same dosing criteria 
as above. For spontaneously aborted episodes (eg, ‘false’ prodromes where symptoms have 
resolved and the subject no longer believes that they are having an impending CVS emetic episode 
by the time the HCP arrives), the subject may decline dosing and the randomization sequence will 
not advance.
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TAK-951
Study ID TAK-951-1501
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Protocol 
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CONFIDENTIAL
Postural hypotension is an identified risk for TAK-951 and data from the FIH study
TAK-951-1001 suggest that orthostatic BP and HR changes may occur in some subjects in the first
2 hours postdose as described above. To mitigate this risk, following study drug administration, 
the subject will remain continuously supine or semirecumbent for at least 2 hours with assistance 
(including repositioning in use of emesis basin and bedpan as needed) and monitoring by the 
visiting HCP. No orthostatic vital signs will be assessed immediately before dosing given that 
some subjects may already be in the emetic phase of a CVS episode at the time of dosing, thereby 
limiting their ability to safely and accurately complete them. Orthostatic vital sign measurements 
will be assessed at 2, 4, and 8 hours following dosing as safety assessments for ambulation and at 
the end of HCP monitoring. No orthostatic vital signs will be completed during the first 2 hours 
after study drug administration for the first 20 aggregate doses of study drug/placebo. If 
asymptomatic (for example, no dizziness, lightheadedness, or palpitations) with normal
supine/semirecumbent BP and HR at 2 hours after study drug administration, the subject will be 
allowed to mobilize if desired with the assistance of the HCP, and orthostatic HR/BP will be 
measured if tolerated. However, if a subject reports symptoms consistent with hypotension (for 
example, light-headedness, dizziness, palpitations, or pre-syncope) upon standing, the HCP will 
immediately assist the subject back to a sitting, semirecumbent, or supine position for an 
additional 1 to 2 hours. If no subjects meet criteria for hypotension or orthostatic hypotension (as 
defined above) after the first 20 aggregate doses in the study, then orthostatic BP will be assessed 
at 90 minutes after dosing and eligible subjects will be allowed to mobilize as desired with 
assistance of the HCP as above at that time point for the next 20 aggregate doses. If no subjects 
meet criteria for hypotension or orthostatic hypotension after the first 40 doses in the study with
assessments at both 120 and 90 minutes postdose, then the first postdose orthostatic BP will be 
assessed at 60 minutes after dosing and eligible subjects will be allowed to mobilize as desired 
with assistance of the HCP as above at that time point. 
If a subject develops symptoms suggestive of hypotension or postural hypotension at any time 
following study drug administration, BP and HR will be assessed by the HCP for evidence of 
hypotension and/or tachycardia, which should be managed as per protocol (see Section 10.2.8.4.) 
and local standard of care. The HCP will remain with the subject for continued observation and 
frequent monitoring of vital signs and cardiovascular side effects for at least 8 hours following the 
dose, as specified in Section 3.0. Should the subject experience persistent, stereotypic emesis or 
retching >2 hours after dosing, rescue with eligible medication(s), as defined in Section 7.4, will 
be allowed by self-administration. The informed consent form will detail potential combinatorial 
cardiovascular effects of commonly prescribed rescue medications (as used off-label for CVS in 
standard of care) and TAK-951.
Blinded study drug will not be administered more than 1 hour after the onset of the emetic phase. A 
subject who does not receive a dose due to closure of this 1-hour post-emesis onset dosing window 
for 1 episode will remain eligible for dosing in future episodes if all other dosing criteria are met. 
Subjects who fail to be dosed 2 or more times for any reason may be replaced.
The HCP will remain at the subject’s home for at least 8 hours after dosing to monitor the subject 
and collect additional data. The wearable patch will provide real-time remote continuous single 
lead ECG, vital signs (temperature, HR), and 
 for 8 hours after application. If needed, a 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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telemedicine visit with the investigator/study staff will be scheduled to provide further support to 
the subject and/or HCP during or following the monitoring period. At the close of the 8 hour HCP 
monitoring period, a final set of vital signs will be obtained to assist in the decision for disposition 
of the subject as described in Sections 9.2.4 and 10.2.8.4. 
To evaluate the secondary and exploratory efficacy endpoints, a variety of clinical outcome 
assessment (COA) measures are proposed. Validated COA measures specific to CVS do not 
currently exist but are under development. Please refer to the associated COA contents for full text 
and design of the COA. 
Briefly, subjects will report their symptoms, signs, HRQOL and other outcomes using an ePRO 
diary device. 

During inter-episodic phases, subjects will report entries on CVS related symptoms/signs 
on weekly basis, and HRQOL of physical, mental, and social functioning every 4 weeks. 

During prodromal/emetic phases, subjects will make diary entries approximately hourly, as 
able, to record changes in symptoms (eg vomiting/retching, nausea, abdominal pain and 
headache) over time.

During recovery phases (in the absence of emesis), subjects will make diary entries on
daily basis, to record their remaining symptoms and to respond to check-in question daily 
on resolution (ie. whether back to baseline as defined by the subject). 

At the resolution of each episode, as defined by the subject, the subject will complete a 
global assessment of episode severity, and impact (eg. work/school absence), and return to 
inter-episodic mode for regular (weekly/monthly) entries.
During the HCP observation period (8 hours), the HCP will also complete an eObsRO diary for 
symptoms and signs associated with CVS. Additionally as an exploratory tool, a passive audio 
data recorder as described above, activated by the HCP upon arrival, will collect audio data of 
emesis (vomiting/retching) for approximately 8 hours, the period of HCP monitoring in each CVS 
episode. Patients will also be asked to press a button on a wrist worn wearable device to mark each 
instance of vomiting or retching they experience during the HCP observation period. The 
association between patient and HCP-reported vomiting/retching (via eObsRO and ePRO) and 
audio-recorded vomiting/retching will be assessed to evaluate the feasibility of audio data 
collection as a potential endpoint for future studies. The audio data collected will not be used to 
inform any treatment recommendations or decisions. The association between patient and 
HCP-reported vomiting/retching (via eObsRO and ePRO) and event marker recorded 
vomiting/retching will be assessed to evaluate the feasibility of event marker data collection as a 
potential endpoint for future studies. The event marker data collected will not be used to inform 
any treatment recommendations or decisions. 
As there are many unknowns associated with this first interventional study in CVS patients, 
study-embedded interviews are planned for first 5 subjects and HCPs after the patients’ first CVS 
episode, to assess to what extent the COA plan and approaches meet the needs of patients and 
HCPs and whether there are any significant gaps in design and execution (Appendix D). 
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Study ID TAK-951-1501
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Subjects will be evaluated for safety, tolerability, and efficacy associated with TAK-951 or 
placebo following all CVS episodes. No subject will be dosed more frequently than every 14 days. 
Sparse PK sampling will occur during the times specified in Section 3.0 optional DNA samples  
 will also be collected from subjects that provide consent for collection through a 
separate procedure at the end of study visit.
Safety will be assessed by monitoring for AEs, vital signs, continuous HR and ECG monitoring 
(using wearable patch), and safety laboratory assessments. The site will contact the subject every
~2 weeks (14 days +/- 4 days) to record any treatment related AEs. 
PK sampling times and scheme may vary based on emerging safety, tolerability and available PK 
data, but the maximal number of samples or the maximum time point will not change. Efficacy 
assessments will be descriptive without predefined hypothesis testing.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design
The proposed randomized double-blind, 2-sequence, 4-period repeated crossover design which 
evaluates safety and tolerability of TAK-951 in CVS prodrome mitigates the overall 
cardiovascular safety risk of the study as a whole by limiting the number of required subjects, but 
doubles the amount of data as compared to a typical 2-sequence, 2-period crossover study with a 
balanced design, assuming subjects can complete all 4 periods. This design minimizes both inter-
and intra-subject variability which is unknown but assumed to be high in a heterogenous syndrome 
such as CVS by allowing each subject to serve as their own control. Additionally, the design will 
provide an initial understanding of the rates of placebo effect for CVS that are as yet unknown. 
Expert consultant feedback and clinical guidelines [3,4,8,9] suggest that abortive therapies for 
CVS episodes are generally recommended to be used as early in the prodromal phase as possible; 
however, they are thought to have potential efficacy at preventing or attenuating an attack up to 
approximately 1 hour into the emetic phase. There is significant heterogeneity across the CVS 
patient population both in the duration of prodromes (minutes to hours) with an average of 
approximately 1 hour, and in the reliability and predictability of patients’ prodromes. The primary 
goal of the proposed study is to optimize safety by having the subject closely monitored for safety 
immediately following dosing with active compound or placebo; therefore, we have proposed to 
allow for a window of dosing from late prodrome up to 1 hour after initiation of the emetic phase to 
facilitate the logistics of close monitoring in a decentralized study. Finally, medical and 
recreational cannabis use is prevalent in the adult CVS community (>80%) [9] raising the risk of 
confounding with cannabinoid hyperemesis syndrome (CHS), a controversial clinical entity which 
is not yet clearly accepted in the field as either: 1) a subtype of CVS with a known trigger, or 2) a 
separate syndrome. Rome IV criteria currently define CHS as a related but separate syndrome [1]. 
Heavy cannabis use is typically defined in the field as daily use. Therefore, due to the prevalence 
of cannabis use in this patient population, those subjects who report using cannabis >3 days/week 
will be excluded to limit confounding with CHS.
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TAK-951
Study ID TAK-951-1501
Page 34 of 93
Protocol 
19 November 2021
CONFIDENTIAL
6.2.2
Rationale for Dose
The PK and tolerability of TAK-951 single doses 
in healthy volunteers was evaluated 
and well tolerated in the phase 1 study TAK-951-1001 
6.2.3
Rationale for Endpoints
The PK and safety endpoints are standard for this type of study, are used widely, and are 
recognized as reliable, accurate, and relevant. Additional PK parameters may be calculated if 
deemed necessary for the interpretation of the data. The secondary and exploratory efficacy
endpoints are based on patient experience data and are designed to provide insight into the optimal 
timing and modality for capturing key signs and symptoms of acute CVS episodes while balancing 
subject burden.
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures
For this study, the following procedures are critical: 
!
Timing of dose, BP (semirecumbent and standing), HR (semirecumbent and standing), and 
timing of PK assessments.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1b study of TAK-951 in humans, and the PK and safety, tolerability profiles of the 
compound are still being elucidated. This protocol is written with some flexibility to accommodate 
the inherent dynamic nature of phase 1 clinical studies. Modifications to the dose, dosing regimen, 
and/or clinical or laboratory procedures, as outlined below, may be required to achieve the 
scientific goals of the study objectives and/or to ensure appropriate safety monitoring of the study 
subjects. As such, the following alterations from the currently outlined dose and/or dosing regimen 
may be permitted based on newly available data, but the maximum daily exposure, may not exceed 
that currently outlined in Section 6.2.2:
!
If indicated, these collected samples may also be assayed in an exploratory manner for 
metabolites and/or additional markers.
!
The timing of planned procedures for assessment of safety procedures (eg, vital signs, 
ECGs, safety laboratory tests) may be modified during the study based on newly available 
safety, tolerability, and PK. These changes will not increase the number of study
procedures for a given subject during his/her participation in the entire study.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable 
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TAK-951
Study ID TAK-951-1501
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19 November 2021
CONFIDENTIAL

Additional laboratory safety tests may be added to blood samples previously drawn to 
obtain additional safety information. It is understood that the current study may employ 
some or none of the alterations described above. Any alteration made to this protocol to 
meet the study objectives must be detailed by the sponsor with a protocol amendment and 
institutional review board (IRB)/ ethics committee approval. 
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned visit/interaction (this can 
be a phone contact), discontinues from the study, is lost to follow-up (ie, the investigator is unable 
to contact the subject) or withdraws consent.
6.4.3
Definition of Study Discontinuation
The sponsor may stop the study for any reason.
Study discontinuation because of nonsafety reasons, such as the following: 

A finding (eg, PK, efficacy) from another nonclinical or clinical study using the study 
treatment(s) results in the study being stopped for a non-safety related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a non-safety-related reason. 

The study is stopped because of nonscientific and nonsafety reasons, such as slow 
enrollment. 
Study discontinuation because of safety reasons: 

Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), 
drug(s) of the same class, or methodology(ies) used in this study.
6.4.4
Criteria for Premature Termination or Suspension of the Study
6.4.4.1
Criteria for Premature Termination or Suspension of Study
Stopping rules included for the study for events suspected to be related to TAK-951:

Two or more subjects experience a sinus tachycardia with HR >120 bpm with symptoms of 
palpitations or light-headedness requiring medical intervention, or
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TAK-951
Study ID TAK-951-1501
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
Two or more subjects experience a National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) scale (v5.0) Grade ≥3 hypotension (ie, requiring medical 
intervention), or

Two or more subjects experience any particular event that is a NCI CTCAE Version 5.0 Grade 
≥3 or,

One subject reports a NCI CTCAE Version 5.0 Grade ≥3 vasovagal syncope (fainting or 
orthostatic collapse), or

One subject reports a serious adverse event (SAE) or

One subject experiences a NCI CTCAE Version 5.0 Grade 4 event.
If during the study any of the study stopping criteria are met, further dosing in the study will be 
paused and subject will be discontinued from the study. The safety data will be reviewed by the 
unblinded DMC. A recommendation will be made to continue, modify, temporarily suspend, or 
terminate the study.
6.4.4.2
Procedures for Premature Termination or Suspension of the Study
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
6.4.4.3
Possible Changes to the Procedures to Address Interruptions due to Pandemic 
Outbreak
The following is intended to give guidance about which changes to the procedures could be
accepted in case any study participants or study sites are impacted by the coronavirus disease 2019 
(COVID-19) pandemic outbreak. The guidance takes references from the Food and Drug 
Administration (FDA) Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards, 
March 2020 and the update from 11 May 2020, and the European Medicines Agency Guidance on 
the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 3 
(28/04/2020). As the COVID-19 pandemic outbreak may peak in different regions at different 
times and restrictions implemented by local laws and recommendations may vary, any decision on
procedural changes should be made on a case by case basis following consultation with the
medical monitor, with patient safety as the priority. The study is currently designed with most 
procedures (excluding screening and end of study visit) occurring in the subject’s home with the 
assistance of a HCP.
Study sites will maintain site-specific plans to maintain the health and safety study subjects, site 
staff and other study personnel (ie, including the home HCP) as related to the COVID-19 
pandemic.
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Study ID TAK-951-1501
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In case there are restrictions to conduct procedures as originally planned in consequence to the
COVID-19 pandemic:

Sites will employ all efforts to see subjects as described in the clinical assessments.

In unavoidable circumstances, such as the COVID-19 pandemic, exceptions may be 
granted for:
–
Alternative methods for conducting subject visits with approval by the medical monitor
and/or sponsor. Such instances will be documented in the study records. 
–
These data collected with alternative methods may be handled differently in the final 
data analysis, with this documented in the statistical analysis plan (SAP).

Procedures for clinical laboratory samples:
–
Allow blood draws or other diagnostic tests to be conducted at a local laboratory (or
relevant clinical or office facility) authorized/certified to perform such tests routinely.
–
Allow the use of web-based back-up system on electronic devices.
–
Deviations from the protocol (eg, missing required bloodwork, visit performed outside 
of window) will be noted as a protocol deviation related to COVID-19.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including laboratory test results, need to be confirmed before the first dose of 
study drug as outlined in the Schedule of Study Procedures in Section 3.0.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements and is eligible for the study.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written or electronic, informed consent form and any required privacy authorization before 
the initiation of any study procedures.
3. The subject is male or female and aged 18 to 50 years, inclusive. 
4. The subject has at least a 1-year history of CVS diagnosis based on the Rome IV diagnostic 
criteria.
5. The subject has had at least 4 CVS episodes over 6 months before screening during the last 
12 months.
6. If taking eligible medications prescribed for the prophylaxis of CVS, the subject must be 
receiving a stable dose for at least 3 months before screening.
7. The subject is willing and able to exclusively use the protocol rescue medications if needed.
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8. The subject has a stereotypic prodrome with onset ≤4 hours before CVS emetic events.
9. The subject has a body mass index (BMI) between 18 and 32 kg/m2, inclusive.
10. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential agrees to use barrier method of contraception (eg, condom with or without 
spermicide) from signing of informed consent throughout the duration of the study and for 
30 days after last dose OR a surgically sterile female subject, or females of nonchildbearing 
potential with laboratory confirmation of postmenopausal status (ie, follicle-stimulating 
hormone levels >40 mIU/mL) or one of childbearing potential who is sexually active with a 
nonsterilized male partner agrees to use a highly effective method of contraception from 
signing of informed consent throughout the duration of the study and for 30 days after the last 
dose as defined in Section 9.5.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has participated in another interventional study within 4 weeks or 5 half-lives of 
the investigational study drug, whichever is longer, before the screening visit. The 4-week 
window will be derived from the date of the last study procedure and/or AE related to the study 
procedure in the previous study to the screening visit of the current study.
2. The subject has potentially received TAK-951 in a previous clinical study, or has previously 
completed, discontinued, or withdrawn from this study.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or is unable to provide consent (eg, incapacity or potential duress or 
undue influence on informed consent process).
4. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance (including 
medication-induced emesis) to prescription or nonprescription drugs or food, or allergic 
reactions to allowed rescue medication(s).
5. The subject has any condition or abnormality (including laboratory abnormalities), current or 
past, that, in the opinion of the investigator or medical monitor, would compromise the safety 
of the subject or interfere with or complicate the assessment of signs or symptoms of CVS.
6. The subject uses medical or recreational cannabis more than 3 days/week or its usage triggers 
nausea and/or vomiting.
7. The subject has a history of hypotension, autonomic instability, orthostatic hypotension 
(excluding in the context of concurrent dehydration), postural orthostatic tachycardia 
syndrome or a history or presence of 2 or more incidents of syncope within the last 5 years 
before screening.
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Study ID TAK-951-1501
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8. The subject has a history of long corrected QT interval QTc, history of significant cardiac 
arrhythmia, or a history or presence of:
a) A family history of unexplained sudden death or channelopathy; or
b) Brugada syndrome (ie, right bundle branch block pattern with ST-elevation in leads 
V1-V3); or
c) Second-degree atrioventricular block type 2, third degree atrioventricular block, prolonged 
QT interval with Fridericia correction method (QTcF) interval, hypokalemia, 
hypomagnesemia, or conduction abnormalities; or
d) Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome); or
e) Any clinically significant ECG findings or medical history including: long or short QTcF 
(over 450 msec or less than 360 msec), bifascicular block or QRS ≥120 msec or PR interval 
>210 msec at screening; subjects with QTcF >450 msec (up to 470 msec) taking chronic 
tricyclic antidepressants (>3 months) may be enrolled after consultation with the medical 
monitor; or 
f)
The subject has a documented history of sinus bradycardia (<45 bpm), sinoatrial block, 
sinus pause ≥3 seconds, or sinus node dysfunction.
9. The subject has a history of other cardiovascular or cerebrovascular disease as assessed by the 
investigator including: hypertension requiring therapy, or a history or presence of disease such 
as cardiac valvulopathy, myocardial infarction, or stroke.
10. The subject has average semirecumbent SBP <95 or >140 or a DBP <65 mm Hg or >90 mm 
Hg at screening. Note: See Section 6.1 for specific cardiovascular criteria that must be met 
immediately before the dose for dosing eligibility.
11. The subject has a screening average HR <55 or >100 bpm; athletic subjects with a HR <55 
bpm may be enrolled based upon the investigator’s judgement provided that HR is >45 bpm 
and rhythm is sinus bradycardia. See Section 6.1 for specific cardiovascular criteria that must 
be met immediately before the dose for dosing eligibility.
12. The subject has orthostatic hypotension defined as a decrease in systolic BP ≥20 mm Hg or a 
decrease in diastolic BP ≥10 mm Hg after approximately 3 minutes of standing when 
compared with BP from the semirecumbent position, at screening. 
13. The subject has postural orthostatic tachycardia, defined as an increase of 30 bpm or HR >120 
bpm after standing for approximately 3 minutes, at screening. 
14. The subject is taking medications commonly associated with tachycardia, palpitations, or 
hypotension as potential adverse effects (eg, beta blockers, nitrates, sildenafil).
15. The subject is taking medications prescribed for the prophylactic management of CVS with 
possible safety or tolerability interactions with TAK-951 as determined by the investigator(s). 
As above, chronic (>3 months) consistent doses of tricyclic antidepressants are allowed after 
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Study ID TAK-951-1501
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CONFIDENTIAL
consultation with the medical monitor if QTcF is <470. The use of prochlorperazine and/or 
promethazine as a rescue medication is explicitly prohibited until >30 hours (5 half-lives of 
TAK-951) after IP administration.
16. Subject has a history of or suspected autonomic dysfunction. 
17. The subject has active neoplastic disease or history of neoplastic disease within 5 years of 
screening visit (except for basal or squamous cell carcinoma of the skin or carcinoma in situ of 
the uterine cervix that has been definitively treated with standard of care approaches) and has 
received treatment in the last 5 years.
18. The subject has a history of requiring ER/urgent medical treatment and intravenous fluid 
therapy for management of dehydration associated with clinically relevant hypotension for >2 
CVS episodes in the last 6 months.
19. The subject has a history of other conditions associated with episodic emesis including: type 1 
diabetes mellitus, type 2 diabetes mellitus, gastroparesis, gastrointestinal dysmotility,
inflammatory bowel disease, eosinophilic esophagitis, rumination, severe functional 
dyspepsia, severe gastrointestinal reflux disease, large (>3 cm) hiatal hernia, or unrepaired
intestinal malrotation. 
20. The subject has taken opiate medications for more than 3 days in the last month. 
21. The subject has a progressive neurological disorder or a structural disorder of the brain from 
birth, trauma or past infection. 
22. The subject has an uncontrolled psychiatric disorder, to include history of suicide attempt, 
active major depressive disorder or severe panic disorder, or at the discretion of the 
investigator(s), for any clinically significant psychiatric history that would likely interfere with 
full participation in the study.
23. The subject has started a nonpharmacologic prophylactic approach (eg, acupuncture, 
biofeedback, chiropractic methods) within 1 month before initiation of the treatment period.
24. The subject has a history of substance abuse.
25. The subject has a positive pregnancy test or plans to become pregnant during the study period. 
26. The subject is a pregnant or lactating/nursing female.
27. The subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to TAK-951 
r to any other ingredients of the 
investigational product.
28. The subject has a clinically unstable disease or condition.
29. The subject has any disease or condition that could compromise the function of those body
systems as assessed by the investigator that could result in altered absorption, excess 
accumulation, or impaired metabolism or excretion of the test medications (eg, mild, moderate 
or severe renal impairment [ie, estimated creatinine clearance <90 ml/min, CrCL]) and/or 
hepatic function as assessed by the investigator (eg, alanine aminotransferase [ALT] >2× the 
Property o
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Study ID TAK-951-1501
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CONFIDENTIAL
upper limit of normal [ULN], total bilirubin [TB] >1.5× ULN, alkaline phosphatase >1.5× 
ULN).
30. The subject has known or suspected active COVID-19 infection as assessed by the 
investigator. 
7.3
Excluded Medications, Supplements, Dietary Products
Subjects must be instructed not to take any new medications without first consulting with the 
investigator. Intermittent triptan therapy (eg, sumatriptan) for management of acute migraine 
headache is allowed but subjects will not be eligible for dosing during a CVS episode if a triptan 
has been taken within 24 hours of a CVS prodrome onset. See Section 7.2 for other excluded 
medications including: medications commonly associated with tachycardia, palpitations, or 
hypotension as potential adverse effects (eg, beta blockers, nitrates, sildenafil),any medications 
prescribed for the prophylactic management of CVS with possible safety or tolerability 
interactions with TAK-951 as determined by the investigator(s). As above, chronic (>3 months) 
consistent dose of tricyclic antidepressants is allowed. The use of prochlorperazine and/or 
promethazine as a rescue medication is explicitly prohibited until >30 hours after IP dosing.
7.3.1
Caffeine
Caffeinated beverages or xanthine-containing products will be limited to amounts of no more than 
6 units per day (1 unit = 120 mg of caffeine).
7.3.2
Diet, Fluid and Activity
There are no specific restrictions on diet and fluids associated with this study. 
7.4
Rescue Therapy
If deemed necessary to manage ongoing CVS symptoms more than 2 hours after 
TAK-951/placebo is given, the subject may elect to self-administer guideline-recommended CVS 
abortive medications as prescribed including: ondansetron 8 mg orally/sublingual OR aprepitant 
125 mg orally, and/or sumatriptan 20 mg nasal spray/SC [9]. The use of prochlorperazine and/or 
promethazine is explicitly excluded due to associated risks of falls and/or orthostatic hypotension 
until >30 hours (5 half-lives of TAK-951) after IP administration. After the completion of the HCP 
monitoring period, the subject may self-administer sedative medications (eg. diphenhydramine, 
benzodiazepines) as prescribed by their CVS provider. Date, timing, dose and medication name 
will be recorded in the eCRF and/or ePRO. 
7.5
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 eCRF using the following categories:

Pretreatment event or AE. The subject has experienced a pretreatment event or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
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Study ID TAK-951-1501
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subject’s health or the subject is unwilling to continue because of the pretreatment event or 
AE.

Liver function test (LFT) abnormalities that meet the following criteria:
–
ALT or aspartate aminotransferase (AST) >3 times the ULN in conjunction with elevated 
total bilirubin >2 times the ULN deemed to be treatment-related.

Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.

Lost to follow-up. The subject did not report to the HCP and at least 3 attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented in the subject’s 
source documents.

Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.

Protocolized withdrawal. The subject may be removed from the study due to no CVS episode 
within 10 weeks following randomization or each subsequent study episode, or the subject has 
2 or more episodes that do not meet criteria for dosing.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy should 
not be recorded in the “voluntary withdrawal” category.

Study termination. The sponsor, IRB, or regulatory agency terminates the study.

Pregnancy. The subject is found to be pregnant. Note: If the subject is found to be pregnant, the 
subject must be withdrawn immediately.

Any subject identified with COVID-19 infection during the study.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit.
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7.7
Subject Replacement
If a subject discontinues from the study, does not have a CVS episode within 10 weeks of 
randomization or the most recent study episode, or is unable to receive timely dosing per protocol 
for >2 episodes, a replacement subject may be enrolled, if deemed appropriate by the investigator 
and sponsor. The study site should contact the sponsor for the replacement subject’s treatment 
assignment and allocation number.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
In this protocol, the term study medication refers to all or any of the drugs defined below. 
TAK-951 SC injection and matching placebo injection will be provided to the site by the sponsor.
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. 
Study drug will be packaged to support enrollment and replacement of subjects as required.
The study site will be supplied by the sponsor with the following medication in a double-blinded 
manner:
8.1.1
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.
The study site will provide the subject with a kit that will contain the next episode's randomized 
blinded dose. The HCP will have materials for administration (needle and syringe, alcohol pads 
and sharps container). As necessary, resupply should be provided as soon as practical after the 
subject recovers from the prior episode (ie, to ensure that subject has study drug for the next 
episode). 
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.2
Placebo 
Matching placebo vial for TAK-951 will be provided by the sponsor.
8.1.3
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers in accordance with local regulatory
requirements.
Property of Takeda: For Non-Commercial 
Only and Subject to the Applicable Terms of Use
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8.1.4
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. The blinded study 
drug/placebo will be dispensed at the site and then provided to the subject and maintained at -25 
degrees C to -15 degrees C with protection from light in the subject's home until use. 
Refer to the pharmacy manual for detailed information and instruction about the storage and 
handling of study drug at investigational sites and the subject's home.
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.
8.1.5
Clinical Study Drug Blinding
This is a double-blind study: the investigator, HCP, sponsor, and subjects are blinded to treatment 
assignment. Randomization code/disclosure envelopes or lists will be provided per the standard 
operating procedures of the study site.
8.1.6
Randomization Code Creation and Storage
All randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.1.7
Clinical Study Blind Maintenance/Unblinding Procedure
The study drug blind will be maintained through a randomization schedule held by the unblinded 
pharmacist or their delegate at the study site or by the sponsor. 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. If possible, the medical monitor should be contacted before the 
blind is broken. Unblinding will be performed per the standard operating procedures of the study 
site.
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy must ensure that the sponsor or 
contract research organization supplied drug is used in accordance with the protocol and pharmacy 
manual and is dispensed only to subjects enrolled in the study. To document appropriate use of the 
sponsor supplied drugs (TAK-951 vials), the investigator pharmacy/site must maintain records of 
drug delivery to the site, site inventory, dispensation and use by each subject, and return to the 
sponsor or designee. The subject will return any unused vial/supplies. 
Upon receipt of sponsor-supplied drug, the designated blinded pharmacist must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, designated site 
pharmacist should acknowledge the receipt of the shipment by signing bottom half of the packing 
list. If there are any discrepancies between the packing list versus the actual product received, 
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Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
Proper drug accountability includes, but is not limited to:

Monitoring expiration dates.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for each prepared dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the schedule of study procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Appendix B.
9.1.1.1
Assignment of Screening and Randomization Numbers 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event. Sponsor or their delegate’s approval is required for rescreening subjects. 
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another 
subject. A single subject cannot be assigned more than 1 randomization number.
9.1.1.2
Study Drug Assignment
Subjects will be randomized to study treatment after the screening visit is complete and before 
prodrome initiation. Subjects who meet screening criteria will be assigned a randomization 
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number in even allocation amongst randomized sequence groups. The randomization number 
encodes the subject assignment to either TAK-951 or placebo, according to the randomization 
schedule generated before the study. Each subject will be dispensed blinded study drug, labeled 
with his/her unique randomization number, throughout the study.
9.1.2
Inclusion and Exclusion
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.3
Medical History/Demography
Qualified study personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the clinical site’s standard of care and appropriate clinical judgment, and 
subject demographics at the screening visit.
Qualified study personnel will review subject prior and concomitant medication use at screening 
and immediately before dosing. Medications are defined as prescription and over-the-counter 
drugs, vaccines, supplements, nutraceuticals, and oral herbal preparations.
9.1.4
Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF. 
Any concomitant medication use must first be discussed with the sponsor, unless the investigator 
or designee considers immediate administration is necessary. The occasional use of 
acetaminophen (approximately <1g/day) is allowed. Explicitly excluded medications are detailed 
in Section 7.3.
There should be no change to these regimens during the study without discussion with the 
principal investigator.
9.1.5
Medication Storage/Procedure Review
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. The subject will 
store the blinded study drug/placebo dispensed from the site in the study-provided research freezer 
within 4 hours of receipt. Each subject’s study freezer will be equipped with a temperature 
monitoring device and temperature excursions will be alerted to the site staff. Specific information 
and instructions will be provided in the pharmacy manual.
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9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
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. Qualified site 
personnel will conduct physical examinations.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed at 
the screening visit and as clinically indicated.
9.2.3
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI = kg/m2). 
The values should be reported to 1 decimal place by rounding. For example, a BMI of 25.63 kg/m2 
would be reported as 25.6 kg/m2. 
9.2.4
Vital Signs
Subjects should rest in a semirecumbent position for at least 3 minutes before vital signs are 
measured. Vital signs will include HR (bpm), respiratory rate, and systolic blood pressure and 
diastolic blood pressure in all parts of the study. All BP and HR assessments should be made in 
duplicate, and the average of both assessments should be used to calculate the final result. The 
HCP can take a third measurement within 10 minutes if there is inconsistency between 
assessments, or, if at screening or before dosing, the physician believes that these are artificially 
high due to subject’s anxiety. Vital signs will be recorded in the eCRF. 
For standing BP and pulse assessment, a BP and pulse assessment will be performed after the 
duplicate semirecumbent assessment has been completed. The subject should stand still for 
approximately 3 minutes before this assessment. Standing assessments must not be performed if 
semirecumbent systolic BP is <85 mm Hg, or if the subject presents with signs or symptoms 
suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry 
vision). Immediately before TAK-951 or matching TAK-951 placebo dosing, subjects who meet 
any cardiovascular criteria will be excluded from dosing during that episode as follows: subjects 
who have a SBP of ≤90 or ≥150 or DBP <60 or >95 mm Hg, or HR ≤50 or ≥110 bpm.
Subjects are instructed and reminded to remain supine/semirecumbent for 2 hours following study 
drug/placebo administration, however the subject may be mobilized after 2 hours if desired if 
orthostatic vital signs are normal and no additional symptoms are present. As detailed in Section 
6.1, earlier mobilization and orthostatic vital sign checks will be considered pending ongoing 
safety data review.
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When vital signs are scheduled at the same time as blood draws, they will be obtained before the 
scheduled blood draw.
Within 30 minutes before the discontinuation of the HCP monitoring at the end of each study 
episode (~8 hours postdose), a final set of vital signs will be obtained between bouts of emesis (if 
ongoing) to determine the subject’s disposition at the end of the HCP monitoring period. 
Preliminary data from Study TAK-951-0001 observational CVS natural history study suggest that 
subjects with CVS may experience significant intermittent tachycardia (>150 bpm) during emetic 
episodes in the absence of TAK-951 pharmacologic effect therefore it is possible that subjects may 
have elevated HR due to the disease itself at close of HCP monitoring if emesis is ongoing. To 
maintain subject safety, vital sign criteria to guide disposition decision making are defined below. 

If predose HR, supine and standing BP criteria are met and the subject is cardiovascularly 
stable (asymptomatic), then the HCP will discontinue the wearable patch, audio recording 
device, and event marker, complete the final study assessments and depart as scheduled.

If HR and/or BP criteria are outside the defined predose parameters (as described above in 
Section 9.2.4), then the investigator must be contacted to determine safe disposition of the 
subject and identify if a transfer of care is necessary. The medical monitor should be 
informed if transfer of care is deemed necessary.
Transfer of Care

If at any time during a dosed study episode (during HCP monitoring or within 5 half-lives 
of TAK-951 [~30 hours]), the HCP or investigator have concern regarding the subject’s 
safety in the home setting, the investigator should determine safe disposition of the subject 
and identify if transfer of care (eg, emergency medical service EMS transport to local 
health care facility) is necessary. The investigator may elect to use telemedicine 
assessment of the subject to facilitate this decision. The medical monitor should be 
informed as to the final decision. If present, the HCP will remain with the subject until 
transfer of care occurs if one is deemed necessary. Subjects who require transfer of care 
will be withdrawn from the study. 
9.2.5
12-Lead ECG
9.2.5.1
Screening and Safety ECG
A 12-lead ECG will be collected at the time points specified in the Schedule of Study Procedures 
(see Section 3.0). 
The investigator will interpret the safety ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded.
The following parameters will be recorded on the eCRF from the subject’s ECG trace: HR, 
respiratory rate interval, QRS interval, PR interval, QT interval, and QTcF.
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The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report.
Ad hoc 12-lead ECGs will also be required, if:
!
the subject’s resting HR is greater than 120 bpm, 
!
if the subject complains of palpitations, dizziness, breathlessness, chest tightness or any
other symptoms suggestive of arrhythmia for >2 minutes OR 
!
if the subject’s resting HR is >140 bpm without symptoms for >2 minutes. 
The ECG, BP and pulse measurements will be reviewed by the investigator, who will use clinical 
judgment regarding further monitoring and management.
9.2.5.2
Telemetry
Cardiac monitoring (HR and single-lead ECG) will be assessed via a wearable patch and will be 
performed before dosing through to approximately 8 hours postdose. The HCP, investigator and 
medical monitor will have access to real-time tracings from the single lead ECG to monitor 
subject.
9.2.5.3
 Audio Data, Event Marker, 
The wearable patch will provide real-time remote 
 for ~8 hours after application. 
 In addition, the HCP will activate a passive recording device for audio data collection of 
retching and emesis for the duration of the HCP's stay in the subject’s home (~8 hours). The audio 
data collected will not be used to inform any treatment recommendations or decisions. The subject
will don a wrist-worn event marker as soon as possible after the identification of the onset of the 
prodrome to capture the number of vomiting/retching events and will wear through the duration of 
the HCP’s stay in the home (~8 hours) for exploratory data collection. 
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9.2.6
Study Drug Administration
Study Drug (TAK-951) will be administered SC as shown in the Schedule of Study Procedures in 
Section 3.0.
9.2.7
AE Monitoring
AE monitoring begins after signing of the informed consent form. Changes in subject health status 
from the baseline assessment until study drug administration should be captured in the subject’s 
medical history. These will be recorded as pretreatment AEs. Of note, during episodes, the HCP 
and study staff will be exclusively responsible for recording and managing identified AEs. The 
audio data recording is not intended to be used for AE capture and will be analyzed after study 
completion however any identified AEs during annotation will be noted and cross checked with 
HCP/eCRF documentation. A complete description of AE collections and procedures is provided 
in Section 10.0.
9.2.8
Efficacy/COA Measurement 
COA measurements in this study consist of PRO, ObsRO, and digital markers; 1) PRO measures 
include CVS related symptoms/signs, HRQOL and other outcomes on patients; 2) ObsRO 
measures include what HCP may observe on subjects such as emetic events, patient’s ability to 
communicate/respond, general impression, and so on; 3) Digital markers may include audio 
information and event marking from patients to record vomiting/retching.
As several symptoms and signs (nausea, emesis, abdominal pain, and headache) may be collected 
from more than 1 source, a validation analysis of all endpoints (with data collected via ePRO, 
eObsRO, or audio recording device) will be conducted to determine the future COA measurement 
strategy. The analysis will examine the correlations among each measure as well as concordance 
of outcomes (eg, emesis counts), to identify and determine outcome(s) reliable for the future use. 
The full text of the scales and questionnaires can be found in the TAK-951-1501 
Clinical Outcome Assessment Scales and Questionnaires.
9.2.8.1
Assessment of Nausea 
Nausea (defined as the desire to vomit without the presence of expulsive muscular movements) 
will be scored using a self-reported, 4-point VRS of “none”, “mild”, “moderate” or “severe.” 
Significant nausea is defined as a VRS ≥ ”moderate”. The presence and severity of 
subject-reported nausea will be recorded in the ePRO and/or reported by the subject to the HCP 
and recorded in the eObsRO. 
9.2.8.2
Assessment of 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 (ePRO, event monitor), HCP (eObsRO) and audio recording. The HCP 
documentation of frequency and timing of emetic events will serve as the primary source for this 
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data during the ~8 hours of HCP monitoring and the ePRO is anticipated to be the primary source 
for this data collection after the departure of the HCP. The correlation between ePRO versus 
eObsRO versus audio recorder tracked emesis events versus event marker will be assessed, in 
addition to the primary analysis on eObsRO versus audio recorder vs event marker. As a 
sensitivity analysis, ePRO (instead of eObsRO) will be tested as the primary outcome.
9.2.8.3
Assessment of Abdominal Pain
Abdominal pain (defined as subjective discomfort localized to the abdominal region) will be 
scored using a self-reported, 4-point VRS ”none”, ”mild”, “moderate”, or “severe” abdominal 
pain. The presence and severity of subject-reported abdominal pain will be recorded in the ePRO.
9.2.8.4
Assessment of Headache
Headache (defined as subjective head discomfort) will be scored using a self-reported, 4-point 
VRS “none”, ”mild”, “moderate”, or “severe” headache. The presence and severity of 
subject-reported headache will be recorded in the ePRO.
Given the exploratory nature of this study and the CVS COA measurements are in the process of 
development, interviews with subjects and HCPs are planned to reflect their experience and 
insights: 1) study embedded interviews after the 1st episode are for the first 5 subjects and their 
HCPs, in order to fill potential gaps in outcomes or other design aspects; 2) study exit interviews 
after study completion for study subjects, to learn their experience on meaningful change on 
treatment effect, study experience, and any gaps. Participation to interviews is all on voluntary 
basis.
9.3
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures as 
detailed in the laboratory manual. Samples will be collected at the time points/windows stipulated 
in the schedule of study procedures (Section 3.0).
9.3.1
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells) with absolute differential
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9.3.2
Chemistry
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride and lipase
Creatinine
Glucose 
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total) if above the upper limit of normal, total bilirubin will be 
fractionated
Protein (total)
Estimated Creatinine Clearance
ALT: alanine aminotransferase; AST: aspartate aminotransferase.
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and 
international normalized ratio) should be performed 24 hours after the abnormality was noted, 
(either at the study site or at an appropriate remote location) and the medical monitor should be 
contacted. 
If ALT or AST remains elevated >3 times the ULN at the 24 hour recheck, the investigator must 
contact the medical monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, and discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE.
Please refer to Section 7.5 for subject discontinuation criteria regarding abnormal liver test results 
and Section 10.2.8.4 for guidance on reporting abnormal liver test results.
9.3.3
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrate
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cell/high-power field, white blood cell/high-power field, and casts.
A urine pregnancy test (beta human chorionic gonadotropin) will be obtained predose in all 
females of childbearing capacity.
9.3.4
Glucose
Blood glucose will be monitored using finger-stick blood samples and will also be monitored 
using safety laboratory testing.
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9.3.5
Diagnostic Screening
Diagnostic Test
HIV
FSH a
Beta-hCG (pregnancy) test
Hepatitis screen (hepatitis B surface antigen and core 
antibody, hepatitis C virus antibody)
Beta-hCG: beta human chorionic gonadotropin; FSH: follicle stimulating hormone for post menopausal women.
Urine
The urine drug screening assessment will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Subjects with positive results for cannabinoids and/or prescribed benzodiazepines or 
amphetamines will not be excluded from the study based on these results.
9.4
PK, Immunogenicity, and DNA Samples
Samples for PK, ADA and DNA (both buccal epithelial cells and whole blood) samples (see table 
below) will be collected as specified in the Schedule of Study Procedures (Section 3.0). Please 
refer to the laboratory manual for information on the collection, processing, and shipment of 
samples to the central laboratory.
#
Specimen Name
Primary 
Specimen
Primary Specimen 
Derivative
Description of Intended 
Use
Sample 
Collection
1
Plasma sample for 
TAK-951 PK
Plasma
NA
Pharmacokinetic 
measurements
Mandatory
2
Buccal epithelial cells 
sample for DNA
Epithelial 
cells
DNA
DNA 
measurements
Optional
3
Whole blood sample for 
DNA
Whole blood
DNA
DNA 
measurements
Optional
4
Serum sample for 
immunogenicity
Serum
NA
Immunogenicity 
assessments
Mandatory
NA: not applicable.
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9.4.1
PK Measurements
Blood samples for plasma PK analysis will be collected as specified in the Schedule of Study
Procedures (Section 3.0). Blood (venipuncture) samples for PK analysis of TAK-951 will be 
collected into chilled blood collection tubes (vacutainer). Please refer to the laboratory manual for 
information on the collection, processing, and shipment of samples to the central laboratory. 
Plasma PK samples may also be used for future pharmacokinetic exploration including metabolite 
characterization and/or further CVS related research evaluations. These data will be used for 
internal exploratory purposes and will not be included in the clinical study report.
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 eCRF. Similarly, it is 
important that the date and time that each blood sample is drawn is accurately recorded in the 
eCRF. 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 eCRF.
9.4.2
Immunogenicity (ADA) Measurements
Protein products have the potential to induce antidrug immune response which may affect the 
safety and efficacy of the compound under study. Detection and analysis of ADA formation is a 
helpful tool in understanding drug immunogenicity, efficacy, and safety. To understand drug 
immunogenicity, blood samples will be collected at screening and at the End of Study visit. 
Samples for ADA will be taken as described in the Schedule of Procedures (Section 3.0).
A 3-tiered ADA testing strategy will be applied to this study. A sample will initially be screened 
for ADA by the ADA screening assay. Any positive sample in the screening assay is considered a 
potential positive, which will be confirmed for true positivity by the confirmatory assay. If a 
sample is confirmed as an ADA true positive, ADA titer will be assessed. The extra 
immunogenicity samples will be stored for future potential further ADA characterization which 
will be dependent on the initial assessment of the effect of ADA status on the observed PK, 
pharmacodynamic, safety, and efficacy profile of TAK-951 in this study as well as the regulatory
request if it is applied.
9.4.3
DNA Measurements
9.4.3.1
Sample for DNA 
Sampling of buccal epithelial cells and whole blood for DNA analysis is optional in this study and 
will only be performed for subjects who provide consent to participate in this assessment. A DNA 
sample may be analyzed 
 from 
each consented subject in the study. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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As DNA research is an evolving science, further assessments may be performed based on newly 
available data and samples will be stored for future analysis.
.
Detailed instructions for collection, storing, handling, and shipping samples will be provided in the 
laboratory manual. 
9.4.4
Confinement
Not applicable.
9.5
Childbearing Status and Methods of Contraception
9.5.1
Women of Childbearing Potential
A woman is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal, unless permanently sterile.
9.5.2
Women of Nonchildbearing Potential
A female subject of nonchildbearing potential is defined as satisfying at least 1 of the following 
criteria:
!
Postmenopausal: At least 12 months of spontaneous amenorrhea and a follicle-stimulating 
hormone (FSH) concentration >40 mIU/mL.
!
Surgically sterile by hysterectomy and/or bilateral salpingectomy, tubal ligation, or 
oophorectomy with appropriate documentation of surgical procedure.
!
Has no uterus as a result of a congenital condition.
9.5.2.1
Contraception for Women of Nonchildbearing Potential
No contraception is required for women of nonchildbearing potential.
9.5.3
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 last dose of study drug, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with or 
without spermicidal cream or jelly). In addition, they must be advised not to donate sperm during 
this period. Females of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception below.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable 
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9.5.4
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, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral salpingotomy or bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. A high FSH level 
in the postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in 
younger women (eg, those 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 males should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are as follows: 

Non-Hormonal Methods: 

Intrauterine device.

Bilateral tubal occlusion.

Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.

Same-sex partners not utilizing assisted reproductive technology.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, 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.
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–
Progestogen-only 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 shorter until she 
has been on contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for female subjects, and all subjects (male and female) will receive 
continued guidance with respect to the avoidance of pregnancy and sperm donation as part of 
the study procedures. Such guidance should include a reminder of the following:
a.
contraceptive requirements of the study
b. reasons for use of barrier methods (ie, condom) in males with pregnant partners
c.
assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last 
visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual 
cycles a pregnancy test must be performed if the answer is “yes”)?
iv. Is there a chance you could be pregnant?
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5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have a negative urine hCG pregnancy test before receiving 
any dose of study medication.
9.5.5
Pregnancy
If any subject is found to be pregnant during the study she must be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose, should also be recorded 
following authorization from the subject’s partner.
If the pregnancy occurs following study drug administration, defined as within 30 days of the last 
dose of active study drug, the pregnancy must be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 15.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject 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 or 
female partner of the subject was participating in a clinical study at the time she became pregnant 
and provide details of the study drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
9.6
Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is withdrawn 
at the screening visit, the investigator should complete the eCRF. The Interdisciplinary Review 
Team should be contacted as a notification of screen failure. The primary reason for screen failure 
is recorded in the eCRF using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other.
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Subject identification numbers assigned to subjects who fail screening should not be reused.
9.6.1
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 eCRF. 
9.6.2
Monitoring Subject Treatment Compliance 
The HCP will administer study drug and record in the eCRF. 
9.6.3
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Section 3.0. 
Assessments should be completed at the designated visit/time point(s).
9.6.4
Screening 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.6 for procedures for documenting screening failures. The 
sponsor or their delegate is required to approve all re-screening requests.
Procedures to be completed at screening include:

Informed consent.

Inclusion/exclusion criteria.

Demographics, medical history, and medication history.

Concomitant medications/therapies.

Physical examination.

Height, weight, BMI, and vital signs (BP, HR, and respiratory rate).

Serum pregnancy test (hCG) for females of childbearing potential.

FSH, if applicable.

Hepatitis B Surface Antigen (HBsAg) and hepatitis C virus.

Screening clinical laboratory tests.

Alcohol breath test.

12-lead ECG.

Pretreatment event/AE assessment.

Home assessment.
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9.6.5
End of Treatment/End of Study Visit 
There will be 1 end-of-treatment/end-of-study visit within 7-10 days after the subject’s final study 
dose or when the subject is terminated from the study, during which the following procedures will 
be performed and documented: 

Concomitant medications/therapies.

AE assessment.

Serum sample for immunogenicity.

Buccal epithelial cells and whole blood DNA sample (optional).
For all subjects who received study drug, the investigator must complete the End of Study eCRF 
page. 
9.6.6
Poststudy Care 
Upon completion of the study, the subject should be returned to the care of a physician and 
standard therapies as required.
9.7
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 3.0. 
Details are provided in the study laboratory manual.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment. In this study, AEs related to the underlying disease (CVS), will not 
be reported as AEs unless they are deemed to be treatment-related SAEs as described in 10.1.1.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease, like those in CVS, should not be 
considered AEs).

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.
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
Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, CVS, asthma, epilepsy), any occurrence 
of an episode should only be captured as an AE if the episodes become more frequent, serious, 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
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Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented. Adverse event(s) 
associated with an overdose will be documented on AE case report forms (CRFs) according to 
Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
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
May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
10.1.2
Special Interest AEs
AEs of special interest for TAK-951 include injection site reactions, immunogenicity,
hypotension, orthostatic hypotension, and tachycardia. These AEs will be monitored by the 
investigator and sponsor.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to NCI CTCAE Version 5.0. AEs not listed by the NCI CTCAE will be graded as 
displayed in Table 10.a.
Table 10.a
NCI CTCAE
Grade
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
2
Moderate; minimal, local, or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living (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.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
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underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Taken with Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).
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
Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until 5 
half-lives of TAK-951 have elapsed, approximately 30 hours after the last dose of investigational 
product. For subjects who discontinue before the administration of study medication, AEs will be 
followed until the subject discontinues study participation. 
10.2.8.2
Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin before the first exposure to 
investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol. All hospitalizations, including those deemed to be related to CVS but 
not TAK951/placebo as well as reasons for admission (ie, intractable nausea/vomiting due to CVS, 
tachycardia, hypotension etc), should be reported to the sponsor however AEs related to the 
underlying study disease (CVS) will not be reported as AEs unless they are deemed to be 
treatment-related SAEs.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.
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
Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 15.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Management of Specific AEs 
Tachycardia
If a subject experiences sustained (>3 minutes) HR >120, the wearable patch will alert the HCP to 
evaluate the single lead ECG tracing to determine heart rhythm. If the HCP is unable to determine 
rhythm based on the single lead ECG tracing, the investigator will be contacted for review and a 
12-lead ECG may be obtained.
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CTCAE Grade 
Management
CTCAE Grade 2 sinus tachycardia (ie, 
Symptomatic a; nonurgent medical 
intervention indicated) with HR 120 and 
above at rest for at least 5 minutes with 
no physical exertion. 
1)CTCAE Grade 2 sinus tachycardia (ie, Symptomatic a; nonurgent 
medical intervention indicated) with HR 120 and above at rest for at least 5 
minutes with no physical exertion) If the HCP is unable to determine based 
on the single lead ECG tracing, the investigator will be contacted for 
review and a 12-lead ECG may be obtained. 
Any CTCAE Grade 3 sinus tachycardia 
(ie, urgent medical intervention 
indicated) or Grade 4 (life-threatening).
2) CTCAE grade 3 and grade 4 (life-threatening): Evaluate 12-lead ECG 
for abnormalities and contact the investigator and call 911 for immediate 
transfer. 
CTCAE: Common Terminology Criteria for Adverse Events; ECG: electrocardiogram; MRD: multiple-rising dose.
a Symptoms may include dizziness, light headedness, chest pain, chest heaviness, palpitations, and shortness of breath.
Suspected 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 
investigator and medical monitor should be contacted. If clinically significant hypotension (SBP 
<90 or DBP<60 with symptoms) develops, the subject should be repositioned in a supine position 
and HR/BP rechecked within 5 minutes. If the BP remains <90/60 with symptoms then the HCP 
will provide immediate treatment (eg, obtaining peripheral intravenous access and administering 1 
liter normal saline (0.9%) by gravity and further immediate care as necessary) and contact the 
investigator. The medical monitor should be informed once immediate care for subject has been 
provided and investigator has been contacted. The subject should be discontinued from the study. 
Injection Site Reaction
If a subject develops a NCI CTCAE Grade 3 (ulceration or necrosis; severe tissue damage, 
operative intervention need) or 4 (life-threatening consequences; urgent intervention indicated) 
discontinue administration of TAK-951, contact the investigator and medical monitor and call 911 
for immediate transfer.
Hypersensitivity
If anaphylaxis or other serious allergic reactions occur, TAK-951 administration will be 
discontinued immediately and appropriate management initiated (eg, epinephrine, and 
antihistamines, and further immediate care as necessary) and call 911. 
Abnormal LFTs
If a subject is noted to have ALT or AST >3× ULN and total bilirubin >2× ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.3 must also be 
performed. 
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10.2.9
Safety Reporting to Investigators, IRBs or Independent Ethics Committees, and 
Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, investigators and IRBs or independent 
ethics committee (IECs), as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further provision to 
the sponsor or sponsor’s designee, suspected unexpected serious adverse reactions will be 
submitted within 7 days for fatal and life-threatening events and 15 days for other serious events, 
unless otherwise required by national regulations. The sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk assessment 
of an investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the study. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
11.0
STUDY-SPECIFIC COMMITTEES 
11.1
External DMC 
An external independent DMC will conduct ongoing reviews of safety data. 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
STATISTICAL METHODS
12.1
Statistical and Analytical Plans
A SAP will be prepared and finalized before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all study 
objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, or appropriateness of the 
planned statistical methods.
Separate documents will also be prepared, including psychometric SAP and study plan (including 
discussion guide) for embedded and exit interviews. 
12.1.1
Analysis Sets
12.1.1.1
Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized and received at least 1
dose of study medication. Subjects will be analyzed according to their randomized treatment, 
regardless of whether they receive an investigational product that is different from that to which 
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they were randomized. Subjects who were randomized but never dosed and were replaced will be 
excluded from the efficacy analysis.
12.1.1.2
Per Protocol Analysis Set
The per protocol analysis set 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 analysis set will be made before the unblinding of the study. 
Analyses using the per protocol analysis set will be provided as a sensitivity analysis.
12.1.1.3
Safety Analysis Set
The safety analysis set will include all subjects who were randomized and received at least 1 dose 
of study medication. Subjects will be analyzed according to the treatment they actually received.
12.1.1.4
PK Set
The PK analysis set will consist of all subjects who receive at least 1 dose of study medication and 
have at least 1 measurable plasma concentration sample.
12.1.1.5
Immunogenicity Set
The immunogenicity analysis set consists of subjects who receive at least 1 dose of study 
medication and have ADA status assessment at baseline, and at least 1 postbaseline sample.
12.1.2
Analysis of Demography and Other Baseline Characteristics
Descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum) will be generated for continuous demographic variables and baseline characteristics 
variables (eg, age, height, weight, and BMI) for placebo group and TAK-951 using the FAS. The 
number and percentage of subjects in each class of the categorical demographic variables and 
baseline characteristics variables (eg, gender, ethnicity, race) will be tabulated. Individual subject 
demographic and baseline characteristics data will be listed.
12.1.3
Efficacy Analysis
The efficacy analyses will be conducted using the FAS. Sensitivity analyses based on the per 
protocol analysis set will be performed for selected secondary efficacy endpoints (eg, data 
collected via ePRO and eObsRO devices). Nominal p-values will be presented when appropriate. 
All efficacy data within the first 30 minutes immediately following TAK-951/placebo 
administration will be excluded from the efficacy analysis to allow for inclusion of those subjects 
who are dosed after the onset of the emetic phase, and for study drug/placebo to be given up to 1 
hour into the emetic phase where subjects may already be experiencing severe, repeated bouts of 
emesis.
In addition to this study protocol, a separate psychometric analysis plan will be developed to detail 
the COA evaluation methods of the COA endpoints. 
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Secondary Efficacy Endpoints
Binary secondary efficacy endpoints to be assessed at 2, 4, and 8 hours include:

Total response (Yes/No), defined as no emesis, no nausea (verbal rating scale [VRS] “none”) 
and no need for rescue therapy before each timepoint (by both ePRO and eObsRO inclusive). 

Absence of significant nausea (Yes/No), defined as VRS of “none” or “mild”, before each 
endpoint (ePRO).

Absence of emesis (Yes/No), defined as no emesis and no need for rescue medication before 
each timepoint (by both ePRO and eObsRO inclusive).
The binary secondary efficacy endpoints will be summarized by treatment groups as observed. 
Treatment difference between TAK-951 and placebo at each scheduled timepoint will be 
estimated and the associated 95% CI will be constructed using normal approximation. These 
binary efficacy endpoints will be analyzed using a nonlinear mixed effects model (NLMEM) with 
repeated measures with treatment, sequence, period, treatment-by-timepoint interaction, and 
treatment-by-timepoint-by-period interaction as fixed effects and subject-within-sequence as a 
random effect based on the observed data as the main analysis method. The odds ratio between 
TAK-951 and placebo at each scheduled timepoint (ie, 2, 4, and 8 hours postdose), the associated 
95% CI and nominal p-value obtained from the nonlinear mixed effects model will be presented. 
Binary efficacy endpoints may also be analyzed using generalized linear mixed effects model with 
fixed effects of sequence, treatment and period with random effect of subject modeled with a no 
diagonal factor analytic (FA0(2)) covariance structure with residual covariance matrix modeled by 
variance component grouped by treatment. Model based estimates comparing treatments along 
with corresponding CI in case the NLMEM model does not fit. Details will be provided in the 
SAP.
Longitudinal continuous secondary endpoints include: 

Peak nausea VRS score at 0, 1, 2, 4, and 8 hours postdose in subjects who have not received 
rescue medication before the evaluation timepoint (ePRO). Data will also be collected at 3, 
5, 6, and 7 hours postdose as able.

Change in nausea VRS score at 1, 2 hours in all subjects and 4, and 8 hours postdose as 
compared to predose score in subjects who have not received rescue medication before the 
evaluation timepoint. Data will also be collected at 3, 5, 6, and 7 hours postdose as 
able(ePRO).

Status of subject’s ADA assessment (ie, ADA-negative or ADA positive, and low or high 
ADA titer).
The longitudinal continuous secondary endpoints will be analyzed using mixed effects model with 
repeated measures (MMRM) as observed. This MMRM model will include treatment, sequence, 
period, timepoint, treatment-by-timepoint interaction and treatment-by-timepoint-by-period 
interaction as fixed effects, and subject-within-sequence as a random effect. Point estimates, the 
associated 95% CIs and nominal p-values for treatment difference between TAK-951 and placebo 
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will be presented at 0, 1, 2, 4, and 8 hours postdose for peak nausea VRS score, and at 1, 2, 4, and 
8 hours postdose for change in nausea VRS score. Missing VRS score will not be imputed. The 
analysis timepoints (0, 1, 2, 4, and 8 hours postdose) will be derived based on the actual time for 
the nausea VRS assessment taken relative to the time of dosing within each period. Missing data 
by subject and HCP may be examined at each time point as well as by treatment assignment.
Exploratory Endpoints
The exploratory endpoints include:

Number of emeses by hour (eg 0-1h, 1-2h, 2-3h, etc) (ePRO, eObsRO, event marker, audio 
recording).

Absence of emesis within 2 hours postdose (Yes/No) (event marker, audio recording).

Absence of emesis within 4 hours postdose (Yes/No) (event marker, audio recording).

Absence of emesis within 8 hours postdose (Yes/No) (event marker, audio recording).

Time from dose to first emetic event (vomiting or retching), if dosed during the prodromal 
period (ePRO, eObsRO, event marker, audio recording).

Total duration (min) of CVS episode, defined as time from study dose to 
subject-determined resolution of recovery phase (ePRO).

Abdominal pain (peak score) at 0, 1, 2 hours in all subjects and 4, and 8 hours postdose in 
subjects who have not received rescue medication before the evaluation timepoint (ePRO). 
Data will also be collected at 3, 5, 6, and 7 hours postdose as able.

Headache (peak score) at 0, 1, 2 hours in all subjects and 4, and 8 hours postdose in 
subjects who have not received rescue medication before the evaluation timepoint (ePRO). 
Data will also be collected at 3, 5, 6, and 7 hours postdose as able.

HRQOL PROMIS-29 (ePRO) at baseline and every 4 weeks in inter-episodic phases.

Number of emergency department visits for CVS per CVS episode (Yes/No)(as defined by 
onset of prodrome in 1 study episode to subject’s definition of resolution of that episode) 
(ePRO, eCRF).

Number of hospitalizations for CVS per CVS episode (as defined by onset of prodrome in 
1 study episode to subject’s definition of resolution of that episode) (ePRO, eCRF).

Rescue medication usage per CVS episode(Yes/No) (as defined by onset of prodrome in 1 
study episode to subject’s definition of resolution of that episode) (ePRO, eObsRO).

Time from dosing to use of rescue medication (ePRO, eObsRO).

Missed days of school/work due to CVS per CVS episode (as defined by onset of prodrome 
in 1 study episode to subject’s definition of resolution of that episode) (ePRO).

Usability and feasibility of ePRO, eObsRO and audio monitor recording (embedded and 
exit interviews with patients and nurse practitioners).
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!
Subject activity as a proxy for functional disability 
!
Change 
 from baseline (predose) to first emesis in those 
subjects who receive prodromal dosing (wearable event marker).
The exploratory endpoints will be summarized descriptively by treatment groups as observed. 
Descriptive statistics for continuous endpoints will include number of subjects, number of 
observations, mean, standard deviation, median, minimum, and maximum.
Descriptive statistics for binary or categorical endpoints will include count and percentage. The 
time-to-event endpoints (time from dose to first emetic event), will be summarized by treatment 
groups. Subjects without documented events will be censored. Kaplan-Meier (KM) estimates and 
KM plots for appropriate endpoints will be provided.
12.1.4
Safety Analysis
Safety data will be summarized by treatment groups using the safety analysis set. No formal 
statistical testing or inference will be made. 
12.1.4.1
AEs
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 23.0 or higher and will be summarized by System Organ Class and Preferred Term by
treatment groups. Treatment-emergent adverse events will be summarized by treatment groups 
and. The number and percentage of subjects with treatment-emergent adverse events and SAEs 
will be summarized by MedDRA System Organ Class, High Level Term, and Preferred Term 
overall, by severity, and by relationship to study drug for each treatment group.
12.1.4.2
Clinical Laboratory Evaluation
Absolute values including baseline and postdose assessments and change from baseline to 
postdose in clinical safety laboratory tests will be summarized descriptively by treatment groups. 
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be flagged and tabulated. All clinical laboratory data 
will be provided in the data listings.
12.1.4.3
Vital Signs
Absolute values and changes from baseline in vital signs parameters will be summarized 
descriptively for each treatment group. Individual vital sign results meeting the Takeda’s markedly 
abnormal criteria will be flagged and tabulated.
12.1.4.4
ECG
ECG data will be summarized descriptively for each treatment group. Values outside normal 
ranges and potentially clinically significant values will be tabulated.
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12.1.4.5
Other Safety Parameters
Physical examination findings will be presented in the data listings.
Depending on the prevalence of COVID-19 infections and illness in regions where the study is 
conducted, additional analysis may be performed to evaluate the impact of COVID on the safety of 
all participating subjects.
12.1.5
PK Analysis
No formal noncompartmental PK analysis will be performed on concentration-time data. 
Summary statistics of plasma concentrations will be summarized using the PK set. Individual 
concentration data will be included in the listings using the PK set.
A population PK analysis may be conducted, and a more detailed description of these analyses 
may be given in a separate analysis plan. The results of these analyses will not be included in the 
clinical study report and may be a standalone report, if needed.
12.1.6
Immunogenicity Analysis
Immunogenicity data 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.

ADA Negative – defined as subjects who do not have a confirmed positive ADA status in 
any postbaseline assessment.

ADA positive – defined as subjects who have confirmed positive ADA status in any 
postbaseline assessment.

High ADA titer – defined as subjects who have at least 1 postbaseline ADA titer >X (this 
value may change based the actual titer data).

Low ADA titer – defined as subjects whose postbaseline ADA titer numbers are all ≤X 
(this value may change based the actual titer data).
Anti-drug antibody status and titer will be listed by subjects.
For effect of ADA on efficacy, subjects may be summarized within each ADA response status 
(negative, positive, high and low titer).
For effect of ADA on safety, subjects’ incidence of AEs by ADA response status (negative, 
positive, high and low titer) may be provided. Injection-site reactions (preferred term) may also be 
summarized by ADA status. The same analysis may be repeated based on ADA titer.
The relationship between immunogenicity status (ADA and ADA titer) and PK may be explored.
12.2
Interim Analysis and Criteria for Early Termination
An interim analysis (IA) may be conducted during the study as specified in the SAP. Data for 
primary and selected secondary endpoints will be analyzed as part of the IA for internal decision 
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making purposes. The sponsor personnel will not have access to the treatment assignment of 
individual subjects but only the aggregated IA results. Study site personnel and the study subjects 
will remain blinded to the treatment assignment for individual subjects and to the outcome of the 
IA until final database lock. Since this is a phase 1b study, the IA is intended to assist internal 
decision making and does not include a possibility to stop the study for efficacy or futility; there 
will not be alpha level adjustment for the final analysis. Should the sponsor choose to perform such 
an IA, the details would be described in the SAP and/or data access management plan before 
unblinding.
12.3
Determination of Sample Size
The sample size is based on feasibility. The chosen sample size is deemed adequate to assess the 
primary objective of safety in this study.
13.0
QUALITY CONTROL AND QUALITY ASSURANCE
13.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
13.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
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. 
13.3
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, 
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where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 13.1.
14.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP). Each investigator will conduct the study according to 
applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Appendix A. The principles of 
Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities.
14.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
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form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
14.2
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. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before the subject entering 
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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 DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time before analysis. The sponsor should be notified 
of consent withdrawal.
14.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 14.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
14.4
Publication, Disclosure, and Clinical Trial Registration Policy
14.4.1
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 
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information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
14.4.2
Clinical Trial Registration 
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.
14.4.3
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
14.5
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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15.0
ADMINISTRATIVE AND REFERENCE INFORMATION
15.1
Administrative Information
15.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
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15.1.2
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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15.1.3
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
15.1.4
List of Abbreviations
ADA
antidrug antibodies
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AE
adverse event(s)
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CHS
cannabinoid hyperemesis syndrome
COA
clinical outcome assessment
COVID-19
coronavirus disease 2019
CRF
case report form
CVS
cyclic vomiting syndrome
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eObsRO
electronic observer-reported outcomes
ePRO
electronic patient-reported outcomes
EMS
emergency medical service
ER
emergency room
FAS
full analysis set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GABA
γ-aminobutyric acid
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCP
healthcare professional
HR
heart rate
HRQOL
health-related quality of life
IA
interim analysis
Proper
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l Use Only and Subject to the Applicable Terms of Use
ttee
port form
ort for
observer
bserv
nic patie
ic pati
ergency m
ergency
emergen
mer
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ICH
International Conference on Harmonisation
IRB
institutional review board
KM
Kaplan-Meier
LFT
liver function test
MMRM
mixed effects model with repeated measures
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NLMEM`
nonlinear mixed effects model
NRS
numeric rating scale
ObsRO
observer-reported outcomes
PK
pharmacokinetic(s)
PONV
postoperative nausea and vomiting
PRO
patient-reported outcomes
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
TB
total bilirubin
ULN
upper limit of normal
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16.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
Adverse event(s), medical history, and concurrent conditions will be coded using MedDRA. Drugs 
will be coded using the World Health Organization Drug Dictionary.
16.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The investigator must review the data change for completeness and accuracy and must 
sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
16.2
Record Retention
The investigator agrees to keep the records stipulated in Section 16.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. 
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
17.0
REFERENCES
1. Aziz I, Palsson OS, Whitehead WE, Sperber AD, Simren M, Tornblom H. Epidemiology, 
Clinical Characteristics, and associations for Rome IV functional nausea and vomiting 
disorders in adults. Clin Gastroenterol Hepatol 2019;17(5):878-86.
2. Bhandari S, Jha P, Thakur A, Kar A, Gerdes H, Venkatesan T. Cyclic vomiting syndrome: 
epidemiology, diagnosis, and treatment. Clin Auton Res 2018;28(2):203-9.
3. Hayes WJ, VanGilder D, Berendse J, Lemon MD, Kappes JA. Cyclic vomiting syndrome: 
diagnostic approach and current management strategies. Clin Exp Gastroenterol 
2018;11:77-84.
4. Li BUK, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, et al. North American 
Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the 
diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 
2008;47(3):379-93.
5. Venkatesan T, Levinthal DJ, Tarbell SE, Jaradeh SS, Hasler WL, Issenman RM, et al. 
Guidelines on management of cyclic vomiting syndrome in adults by the American 
Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association. 
Neurogastroenterol Motil 2019;31(Suppl 2):e13604.
adults: the illness, the patients, and problems of management. BMC Med 
2005;3(20):1741-7015-3-20.
9. Venkatesan T, Sengupta J, Lodhi A, Schroeder A, Adams K, Hogan WJ, et al. An internet 
survey of marijuana and hot shower use in adults with cyclic vomiting syndrome (CVS). Exp 
Brain Res 2014;232(8):2563-70.
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APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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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 signing the informed consent and throughout the duration of the study, and for 
30 days after the last dose of study drug. 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 
the last dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, the investigator will offer the subject the choice to receive unblinded treatment 
information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Overview of Study Design for TAK-951-1501 Trial Embedded and Exit 
Interviews 
Two rounds of voluntary interviews with subjects and HCPs have been planned during and after
the TAK-951-1501 trial.

The first round is the Embedded Interview, which will take place following the first episode 
with up to the first 5 volunteering subjects and their paired HCPs. The purpose of embedded 
interview is to detect in a timely manner any potential issues or gaps in eCOA and other design 
aspects of TAK-951-1501 study. The findings of embedded interviews may inform protocol 
amendments. 

The second round is the Exit Interview, which will take place following the completion of 
subject’s main trial activities, with up to all 20 subjects and their paired HCPs. The purpose of 
exit interview is to identify additional issues or gaps, obtain direct and in-depth input from 
patients on their treatment experience (eg, how they define a “meaningful change”) and from 
HCPs on their trial experience to inform future trial design.
Participation of both interview rounds will be on voluntary basis. All interviews will be conducted 
as 1:1 via telephone. There will be 4 interview types: 1) embedded interview for subjects, 2) 
embedded interview for HCPs, 3) exit interview for subjects, and 4) exit interview for HCPs.
Separate semi-structured interview guides will be prepared for each of the 4 interview types, as 
described below:
1) Subject embedded interview guide: will be used to understand their trial experience from 
randomization to the completion of the first episode, assess subject’s ability to use and 
complete the eCOA (particularly to detect difficulties or challenges with details), and collect 
their feedback on individual item level for the eCOA. Up to 5 subjects will be asked about the 
feasibility of the initial study visit (eg, with specifics about their recording of symptoms and 
other outcome changes during the first episode, their experience with the HCP’s first at-home 
visit, their use of eCOA device and other monitoring devices).
2) HCP embedded interview guide: will be used to conduct interviews with the paired HCPs for 
the embedded subject interviewees. The discussion will cover the topics such as: their overall 
experience of the first home visit, feedback on study procedure and steps, and feedback on the 
use of eCOA (ie, observing patient use of ePRO, and self-use of eObsRO).
3) Subject exit interview guide: will contain questions about the subject’s overall experience 
with the study process, interpretation on each eCOA item and their perception of “meaningful 
change” from treatment, experience of HCP visits, ease or difficulty with trial-involved 
devices, and other feedback on the clinical trial as a whole. 
4) HCP exit interview guide: in addition to topics asked at the embedded interview, the exit one
will reflect more questions about the HCP’s overall experience with the study process, at-home 
visits, ease or difficulty with completion of study related data entries or forms, as well as 
overall suggestions about conducting interventional study with CVS patients. 
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A qualitative analysis plan (QAP) will be prepared to specify how the interview data will be 
handled and analyzed prior to initiation of the interviews.
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ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
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SAP_001.pdf: 
NCT Number: 
Title: A Randomized, Double-Blind, Placebo-Controlled Repeated Crossover Study to 
Evaluate the Safety and Tolerability of Intermittent Single Doses of TAK-951 in the 
Abortive Treatment of Subjects with Cyclic Vomiting Syndrome.
Study Number: TAK-951_1501
Document Version and Date: Version 1.0 09-SEPT-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. 
Statistical Analysis Plan
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. 
STATISTICAL ANALYSIS PLAN
Study Number: TAK-951-1501
Study Title: A Randomized, Double-Blind, Placebo-Controlled Repeated Crossover Study 
to Evaluate the Safety and Tolerability of Intermittent Single Doses of TAK-951 in the 
Abortive Treatment of Subjects with Cyclic Vomiting Syndrome.
Phase: 1 
Version: 1.0 
Date: 09-SEPT-2021
Prepared by: 
Based on:
Protocol Version: 1.0
Protocol Date: 20-JUL-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
sover S
sover
AK-951 
951
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ome.
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hat no inf
at no 


TAK-951-1501
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Statistical Analysis Plan 
09-AUG-2021
CONFIDENTIAL
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
09-AUG-2021
Not Applicable
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TAK-951-1501
Page 3 of 34
Statistical Analysis Plan 
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CONFIDENTIAL
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................8
1.1
Objectives..................................................................................................................8
1.1.1
Primary Objective..............................................................................................8
1.1.2
Secondary Objective(s)......................................................................................8
1.1.3
Exploratory Objective(s)....................................................................................8
1.2
Endpoints...................................................................................................................8
1.2.1
Primary Endpoint(s)...........................................................................................8
1.2.2
Secondary Endpoint(s).......................................................................................8
1.2.3
Exploratory Endpoint(s).....................................................................................9
2.0
STUDY DESIGN..........................................................................................................10
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................14
3.1
Statistical Hypotheses..............................................................................................14
3.2
Statistical Decision Rules.........................................................................................14
3.3
Multiplicity Adjustment...........................................................................................14
4.0
SAMPLE-SIZE DETERMINATION.............................................................................14
5.0
ANALYSIS SETS.........................................................................................................15
5.1
Safety Analysis Set..................................................................................................15
5.2
Full Analysis Set......................................................................................................15
5.3
Per-Protocol Analysis Set ........................................................................................15
5.4
Pharmacokinetic Analysis Set..................................................................................15
5.5
Immunogenicity Set.................................................................................................15
6.0
STATISTICAL ANALYSIS..........................................................................................15
6.1
General Considerations............................................................................................15
6.1.1
Handling of Treatment Misallocations .............................................................16
6.1.2
Analysis Approach for Continuous Variables...................................................16
6.1.3
Analysis Approach for Binary Variables..........................................................17
6.1.4
Analysis Approach for Time-to-Event Variables..............................................17
6.2
Disposition of Subjects ............................................................................................17
6.3
Demographic and Other Baseline Characteristics.....................................................18
6.3.1
Demographics and Baseline Characteristics .....................................................18
6.3.2
Medical History and Concurrent Medical Conditions.......................................18
6.4
Medication History and Concomitant Medications...................................................18
6.5
Efficacy Analysis.....................................................................................................19
6.5.1
Secondary Endpoint(s) Analysis ......................................................................19
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CONFIDENTIAL
6.5.1.1
Derivation of Endpoint(s) ........................................................................19
6.5.1.2
Main Analytical Approach.......................................................................21
6.5.2
Exploratory Endpoint(s) Analysis ....................................................................21
6.5.2.1
Derivation of Endpoint(s) ........................................................................21
6.5.2.2
Main Analytical Approach.......................................................................23
6.6
Safety Analysis........................................................................................................23
6.6.1
Adverse Events................................................................................................23
6.6.2
Clinical Laboratory Evaluation ........................................................................25
6.6.2.1
Hematology.............................................................................................26
6.6.2.2
Chemistry................................................................................................26
6.6.2.3
Urinalysis ................................................................................................26
6.6.2.4
Diagnostic Screening...............................................................................27
6.6.3
Vital Signs.......................................................................................................27
6.6.4
ECG ................................................................................................................27
6.6.5
Other Safety Parameters ..................................................................................27
6.6.6
Extent of Exposure and Compliance ................................................................28
6.7
Immunogenicity Analysis ........................................................................................28
6.8
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses................................28
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................29
6.9.1
PRO Analysis ..................................................................................................29
6.9.2
Health Care Utilization Analysis......................................................................29
6.10
Interim Analyses......................................................................................................29
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] ............................................................................................................29
7.0
REFERENCES..............................................................................................................29
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................29
9.0
APPENDIX...................................................................................................................30
9.1
Data Handling Conventions .....................................................................................30
9.1.1
Missing Data Handling ....................................................................................30
9.1.1.1
Conventions for Missing Adverse Event Dates ........................................30
9.1.1.2
Conventions for Missing Concomitant Medication Dates.........................31
9.1.1.3
Methods for Handling of Missing Efficacy Data......................................31
9.1.2
Definition of Baseline......................................................................................32
9.1.3
Definition of Visit Windows............................................................................32
9.1.4
Definition of Hour Window.............................................................................32
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CONFIDENTIAL
9.2
Analysis Software....................................................................................................32
9.3
Criteria for Identification of Markedly Abnormal Laboratory Values and Vital 
Sign Values. ............................................................................................................32
9.4
Criteria for Markedly Abnormal Values for Vital Signs ...........................................33
9.5
Criteria for Identification of Markedly Abnormal Orthostatic Changes ....................34
LIST OF IN-TEXT TABLES
Table 6.a
NCI CTCAE ......................................................................................................24
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Statistical Analysis Plan 
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CONFIDENTIAL
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ANCOVA
analysis of covariance
ANOVA
analysis of variance
BOCF
baseline observation carried forward
BMI
body mass index
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019 
CTCAE
Common Terminology Criteria for Adverse Events
CVS
Cyclical vomiting syndrome
DMC
Data Monitoring Committee
IRC
Internal Review Committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
HR
hazard ratio
ITT
intention-to-treat
KM
Kaplan-Meier
LLN
lower limit of normal
LOCF
last observation carried forward
MAR
missing at random
MCAR
missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effects model for repeated measures
MNAR
missing not at random
OC
observed cases
OR
odds ratio
PD
pharmacodynamic
PFS
progression free survival
PK
pharmacokinetic
PPAS
per-protocol analysis set
PRO
patient-reported outcomes
PT
Preferred Term (MedDRA)
Q1
25th percentile
Q3
75th percentile
RD
risk difference
RR
risk ratio
SAE
serious adverse event
SAP
statistical analysis plan
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CONFIDENTIAL
SOC
System Organ Class
TEAE 
treatment-emergent adverse event]
WHODrug
WHO drug dictionary
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TAK-951-1501
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CONFIDENTIAL
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of intermittent single 
SC doses of TAK-951 in subjects with CVS during the prodromal/early emetic phase at home.
1.1.2
Secondary Objective(s)
The secondary objective(s) of the study are:

To evaluate the efficacy of intermittent single SC doses of TAK-951 in subjects with CVS.

To assess the immunogenicity after intermittent single SC doses of TAK-951 in subjects 
with CVS.
1.1.3
Exploratory Objective(s)
Exploratory endpoints of this study include: 

To evaluate the PK of TAK-951 following intermittent single SC doses in subjects with CVS.

To evaluate additional efficacy parameters of intermittent single SC doses of TAK-951 in 
subjects with CVS.
1.2
Endpoints
1.2.1
Primary Endpoint(s)
The primary endpoint of the study is safety and tolerability as assessed through vital signs, 
laboratory assessments, and AEs.
1.2.2
Secondary Endpoint(s) 
The secondary endpoints exclude the first 30 minutes immediately following TAK-951/placebo 
administration. 
The following endpoints will be assessed within 2, 4, 8, 12 and 24 hours postdose: 

Total response (Yes/No), defined as no emesis, no nausea (verbal rating scale [VRS] 
“none”) and no need for rescue therapy before each timepoint (by both electronic reported 
patient-outcomes [ePRO] and electronic observer-reported outcomes [eObsRO] inclusive). 

Absence of emesis (Yes/No), defined as no emesis and no need for rescue medication before 
each timepoint (by both ePRO and eObsRO, inclusive).

Absence of significant nausea (Yes/No), defined as VRS of “none” or “mild” and no need for 
rescue medication before the evaluation timepoint (ePRO).
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TAK-951-1501
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Statistical Analysis Plan 
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CONFIDENTIAL

Peak nausea verbal rating scale (VRS) score at 0, 1, 2 hours in all subjects and 4, 8, 12, 24 
hours postdose without receiving rescue medication before the evaluation timepoint (ePRO). 
Data will also be collected at 3, 5, 6, and 7 hours postdose as able.

Change in nausea VRS score at 1 and 2 hours in all subjects and 4, 8, 12, 24 hours postdose 
as compared with predose score without receiving rescue medication before the evaluation 
timepoint. Data will also be collected at 3, 5, 6, and 7 hours postdose as able (ePRO).

Status of subject’s antidrug antibody (ADA) assessment (ie, ADA-negative or ADA-positive, 
and low or high ADA titer).
1.2.3
Exploratory Endpoint(s)
All exploratory endpoints exclude the first 30 min immediately following TAK-951/placebo 
administration.
Exploratory endpoints will be assessed through the following parameters: 
1. Efficacy
–
Number of emeses by hour (eg 0-1h, 1-2h, 2-3h, etc) (ePRO, eObsRO, event marker, 
audio recording).
–
Absence of emesis within 2 hours postdose (Yes/No) (event marker, audio recording).
–
Absence of emesis within 4 hours postdose (Yes/No) in subjects who have not received 
rescue medication before the evaluation timepoint (event marker, audio recording).
–
Absence of emesis within 8 hours postdose (Yes/No) in subjects who have not received 
rescue medication before the evaluation timepoint (event marker, audio recording).
–
Time from dose to first emetic event (vomiting or retching), within each episode—(ePRO, 
eObsRO, event marker, audio recording).
–
Total duration (min) of CVS episode, defined as time from study dose to subject-
determined resolution of episode (i.e., back to baseline status) (ePRO)
–
Abdominal pain (peak score) at 0, 1, and 2 hours in all subjects and 4, 8, 12, and 24 
hours postdose in subjects who have not received rescue medication before the 
evaluation timepoint (ePRO). Data will also be collected at 3, 5, 6, and 7 hours postdose 
as able.
–
Headache (peak score) at 0, 1, 2 hours in all subjects and 4, 8, 12, 24 hours postdose in 
subjects who have not received rescue medication before the evaluation timepoint 
(ePRO). Data will also be collected at 3, 5, 6, and 7 hours postdose as able.
–
Health-related quality of life (HRQOL) PROMIS-29 at baseline and in inter-episodic 
phase every 4 weeks (ePRO).
–
Number of emergency department visits for CVS per CVS episode (Yes/No) (as defined by 
onset of prodrome in 1 study episode to subject’s definition of resolution of that episode).
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Statistical Analysis Plan 
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CONFIDENTIAL
–
Number of hospitalizations for CVS per CVS episode (as defined by onset of prodrome in 
1 study episode to subject’s definition of resolution of that episode) (ePRO).
–
Rescue medication usage per CVS episode (as defined by onset of prodrome in 1 study 
episode to subject’s definition of resolution of that episode) (Yes/No) (ePRO, eObsRO).
–
Time from dosing to first use of rescue medication within each CVS episode (as defined 
by onset of prodrome in 1 study episode to subject’s definition of resolution of that 
episode) (ePRO, eObsRO).
–
Missed days of school/work due to CVS per CVS episode (as defined by onset of 
prodrome in 1 study episode to subject’s definition of resolution of that episode) (ePRO).
–
Usability and feasibility of ePRO, eObsRO and audio monitor recording (embedded 
interviews after the 1st episode with patients and HHC, and study interviews after the 
completion of this study with patients). Participation to interviews are all on voluntary 
basis.
–
Subject activity as a proxy for functional disability 
–
 from baseline (predose) to first emesis in those 
subjects who receive prodromal dosing (wearable event marker).
2. Individual plasma concentrations for TAK-951.
2.0
STUDY DESIGN
This is a randomized, double-blind, repeat crossover placebo-controlled study to evaluate the 
safety, tolerability, efficacy, PK, and feasibility of episodic administration at home of TAK-
951/placebo in subjects aged 18 to 50 years, inclusive, during the prodromal and early emetic 
phase in subjects with moderate to severe CVS. Approximately 20 subjects will be randomized to 
treatment sequence in this study.
Consented subjects will be screened for eligibility before randomization. Of note, data from 
Study TAK-951-1001 FIH study showed that 34% of healthy volunteers experienced orthostatic 
tachycardia (<5% symptomatic) as defined as >120 beats per minute (bmp) or an increase in 
HR upon standing of >30 bpm, and approximately 13% experienced orthostatic hypotension 
(<5% symptomatic) defined as a decrease upon standing of >20 mm Hg systolic, 10 mm Hg 
diastolic, or both at any time point after dosing with effects lasting approximately 2 to 4 hours. It 
is hypothesized that TAK-951 causes vasodilation that leads to these observed hemodynamic 
changes. At the screening visit, baseline physical examination, medical history including 
cardiovascular history and any history of autonomic dysfunction, safety laboratory tests, ECG, 
vital signs, orthostatic BP and HR will be assessed. Given that CVS may also be associated with 
comorbidities involving autonomic dysfunction, subjects will be screened to exclude baseline 
orthostatic hypotension and postural tachycardia as part of their cardiovascular history and 
vital sign assessments. Before randomization, a telehealth visit with the investigator/home health 
provider/study staff will evaluate the at-home setting for proximity to a visiting home health 
provider, potential drug storage conditions will be assessed for study feasibility, and safety of the 
Property of Takeda: For non-commercial use only and sub
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TAK-951-1501
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Statistical Analysis Plan 
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CONFIDENTIAL
home setting. The remote home screening may not occur same day as physical screening but 
randomization may not occur until both physical and home screening are complete and the 
subject is eligible. Those subjects who are eligible will then be randomized into the study. 
Randomized subjects will use a variety of devices to facilitate their participation in this 
decentralized study including: tablet or hand-held mobile device for ePRO diary, wearable patch 
and accompanying bedside monitor tablet, wrist-worn event marker, audio recording device, BP 
cuff, and glucometer, as well as a small temperature-monitored freezer for drug/placebo home 
storage. 
The at-home portions of the study will be supported by home HCPs (registered nurse, nurse 
practitioner, etc.) who will have a skill set including but not limited to the ability to: monitor 
vital signs, draw/prepare samples for clinical laboratory assessment, place an intravenous line if 
necessary, administer intravenous fluids if indicated, and review a digital rhythm strip if 
indicated.
Approximately 20 subjects will be randomized to treatment sequence in 1 of 4 groups with 
5 subjects per group as outlined in Figure 2.a. in this 4 episode, 12 month randomized, double-
blind, repeat crossover, placebo-controlled study to evaluate the safety, tolerability, efficacy, 
PK, and feasibility of episodic administration at home of TAK-951/placebo. Subjects will receive 
a single dose of TAK 951 or placebo at each of the 4 anticipated CVS episodes over a maximum 
52-week study period in a double-blind manner (subject, sponsor and investigator blinded). 
Subjects who meet stopping criteria will be discontinued from the study and may be replaced by 
another subject. Subjects who do not have a CVS episode within 10 weeks of randomization and 
subjects who withdraw may be replaced in order for approximately 20 subjects to complete the 
study. 
At the initiation of the prodrome (ie, first recognition by the subject of 1 or more of their usual 
symptoms of CVS prodrome) in each of the assessed CVS episodes, the subject will immediately 
contact a study HCP, produce a urine sample if necessary, and remove the blinded dose from the 
freezer to thaw at room temperature. Temperature excursion data supports dose stability up to 
4 hours and dose thaw within 20 minutes at room temperature. 
The HCP will arrive at the subject’s home as rapidly as possible following contact from the 
subject to allow for dosing no later than 1 hour after onset of the emetic phase. The HCP will 
complete predose checks as outlined in the Schedule of Assessments (Section 3.0), initiate the 
wearable patch and wrist-worn wearable device (event marker) and administer double-blind 
study drug/placebo to eligible subjects based on predose vital signs during the continued 
prodrome or no later than 1 hour after the onset of the emetic phase. Upon arrival, the HCP will 
also activate a passive recording device for exploratory audio data collection of retching and 
emesis during the study period. Immediately before dosing in each CVS episode, subjects who 
meet any cardiovascular criteria will be excluded from dosing during that episode as follows: 
subjects who have a BP of ≤90/60 or ≥150/95 mm Hg, or HR ≤50 or ≥110 bpm. Athletic subjects 
with a HR <55 bpm may be enrolled based upon the investigator’s judgement provided that HR 
is >45 bpm and rhythm is sinus bradycardia.
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TAK-951-1501
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Statistical Analysis Plan 
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CONFIDENTIAL
Postural hypotension is an identified risk for TAK-951 and data from the FIH study 
TAK-951-1001 suggest that orthostatic BP and HR changes may occur in some subjects in the 
first 2 hours postdose as described above. To mitigate this risk, following study drug 
administration, the subject will remain continuously supine or semirecumbent for at least 2 
hours with assistance (including repositioning in use of emesis basin and bedpan as needed) and 
monitoring by the visiting HCP. No orthostatic vital signs will be assessed immediately before 
dosing given that some subjects may already be in the emetic phase of a CVS episode at the time 
of dosing, thereby limiting their ability to safely and accurately complete them. Orthostatic vital 
sign measurements will be assessed at 2, 4, and 8 hours following dosing as safety assessments 
for ambulation and at the end of HCP monitoring. No orthostatic vital signs will be completed 
during the first 2 hours after study drug administration for the first 20 aggregate doses of study 
drug/placebo. If asymptomatic (for example, no dizziness, lightheadedness, or palpitations) with 
normal supine/semirecumbent BP and HR at 2 hours after study drug administration, the subject 
will be allowed to mobilize if desired with the assistance of the HCP, and orthostatic HR/BP will 
be measured if tolerated. However, if a subject reports symptoms consistent with hypotension 
(for example, light-headedness, dizziness, palpitations, or pre-syncope) upon standing, the HCP 
will immediately assist the subject back to a sitting, semirecumbent, or supine position for an 
additional 1 to 2 hours. If no subjects meet criteria for hypotension or orthostatic hypotension 
(as defined above) after the first 20 aggregate doses in the study, then orthostatic BP will be 
assessed at 90 minutes after dosing and eligible subjects will be allowed to mobilize as desired 
with assistance of the HCP as above at that time point for the next 20 aggregate doses. If no 
subjects meet criteria for hypotension or orthostatic hypotension after the first 40 doses in the 
study with assessments at both 120 and 90 minutes postdose, then the first postdose orthostatic 
BP will be assessed at 60 minutes after dosing and eligible subjects will be allowed to mobilize 
as desired with assistance of the HCP as above at that time point. 
If a subject develops symptoms suggestive of hypotension or postural hypotension at any time 
following study drug administration, BP and HR will be assessed by the HCP for evidence of 
hypotension and/or tachycardia, which should be managed as per protocol (see Section
10.2.8.4.) and local standard of care. The HCP will remain with the subject for continued 
observation and frequent monitoring of vital signs and cardiovascular side effects for at least 8 
hours following the dose, as specified in Section 3.0. Should the subject experience persistent, 
stereotypic emesis or retching >2 hours after dosing, rescue with eligible medication(s), as 
defined in Section 7.4, will be allowed by self-administration. The informed consent form will 
detail potential combinatorial cardiovascular effects of commonly prescribed rescue medications 
(as used off-label for CVS in standard of care) and TAK-951.
Blinded study drug will not be administered more than 1 hour after the onset of the emetic phase. 
A subject who does not receive a dose due to closure of this 1-hour post-emesis onset dosing 
window for 1 episode will remain eligible for dosing in future episodes if all other dosing criteria 
are met. Subjects who fail to be dosed 2 or more times for any reason may be replaced.
The HCP will remain at the subject’s home for at least 8 hours after dosing to monitor the 
subject and collect additional data. The wearable patch will provide real-time remote continuous 
single lead ECG, vital signs (temperature, HR), and 
 for 8 hours after application. If 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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needed, a telemedicine visit with the investigator/study staff will be scheduled to provide further 
support to the subject and/or HCP during or following the monitoring period. At the close of the 
8 hour HCP monitoring period, a final set of vital signs will be obtained to assist in the decision 
for disposition of the subject as described in Sections 9.2.4 and 10.2.8.4. 
To evaluate the secondary and exploratory efficacy endpoints, a variety of clinical outcome 
assessment (COA) measures are proposed. Validated COA measures specific to CVS do not 
currently exist but are under development. Please refer to the associated COA contents (v1.0) for 
full text and design of the COA. 
Briefly, subjects will report their symptoms, signs, HRQOL and other outcomes using an ePRO 
diary device. 

During inter-episodic phases, subjects may report entries on CVS related symptoms/signs on 
weekly basis, and HRQOL of physical, mental, and social functioning every 4 weeks. 

During prodromal/emetic phases, subjects may make diary entries approximately hourly, as 
able, to record changes in symptoms (eg. vomiting/retching, nausea, abdominal pain and 
headache) over time.

During recovery phases (in the absence of emesis), subjects may make diary entries on daily 
basis, to record their remaining symptoms and to respond to check-in question daily on 
resolution (ie. whether back to baseline as defined by the subject). 

At the resolution of each episode, as defined by the subject, the subject will complete a global 
assessment of episode severity, and impact (eg. work/school absence), and return to inter-
episodic mode for regular (weekly/monthly) entries.
During the HCP observation period (8 hours), the HCP will also complete an eObsRO diary for 
symptoms and signs associated with CVS. Additionally as an exploratory tool, a passive audio 
data recorder as described above, activated by the HCP upon arrival, will collect audio data of 
emesis (vomiting/retching) for approximately 8 hours, the period of HCP monitoring in each 
CVS episode. Patients will also be asked to press a button on a wrist worn wearable device to 
mark each instance of vomiting or retching they experience during the HCP observation period. 
The association between patient and HCP-reported vomiting/retching (via eObsRO and ePRO) 
and audio-recorded vomiting/retching will be assessed to evaluate the feasibility of audio data 
collection as a potential endpoint for future studies. The audio data collected will not be used to 
inform any treatment recommendations or decisions. The association between patient and HCP-
reported vomiting/retching (via eObsRO and ePRO) and event marker recorded 
vomiting/retching will be assessed to evaluate the feasibility of event marker data collection as a 
potential endpoint for future studies. The event marker data collected will not be used to inform 
any treatment recommendations or decisions. 
As there are many unknowns associated with this first interventional study in CVS patients, 
study-embedded interviews are planned for first 5 subjects and HCPs after the patients’ first 
CVS episode, to assess to what extent the COA plan and approaches meet the needs of patients 
and HCPs and whether there are any significant gaps in design and execution. 
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Subjects will be evaluated for safety, tolerability, and efficacy associated with TAK-951 or 
placebo following all CVS episodes. No subject will be dosed more frequently than every 7 days. 
Sparse PK sampling will occur during the times specified in Section 3.0 An optional DNA sample 
will also be collected from subjects that provide consent for collection through a 
separate procedure at the end of study visit.
Safety will be assessed by monitoring for AEs, vital signs, continuous HR and ECG monitoring 
(using wearable patch), and safety laboratory assessments. PK sampling times and scheme may 
vary based on emerging safety, tolerability and available PK data, but the maximal number of 
samples or the maximum time point will not change. Efficacy assessments will be descriptive 
without predefined hypothesis testing.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
No formal statistical hypothesis testing is planned in this study. 
3.2
Statistical Decision Rules
No formal statistical decisions are planned in this study. 
3.3
Multiplicity Adjustment
Not applicable. 
4.0
SAMPLE-SIZE DETERMINATION
The sample size is based on feasibility. The chosen sample size is deemed adequate to assess the 
primary objective of safety in this study.
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5.0
ANALYSIS SETS
5.1
Safety Analysis Set
The safety analysis set will include all subjects who were randomized and received at least 1 
dose of study medication. Subjects will be analyzed according to the treatment they actually 
received.
5.2
Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized and received at least 1 
dose of study medication. 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. Subjects who were randomized but never dosed and were replaced will be 
excluded from the efficacy analysis.
5.3
Per-Protocol Analysis Set 
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 analysis set will be made before the unblinding 
of the study. Analyses using the per protocol analysis set will be provided as a sensitivity 
analysis.
5.4
Pharmacokinetic Analysis Set 
The PK analysis set will consist of all subjects who receive at least 1 dose of study medication 
and have at least 1 measurable plasma concentration sample.
5.5
Immunogenicity Set 
The immunogenicity analysis set consists of subjects who receive at least 1 dose of study 
medication and have ADA status assessment at baseline, and at least 1 postbaseline sample.
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
All data for randomized subjects will be presented in by-subjects listings, sorted by sequence, 
subject ID, treatment, period, and timepoint. 
Data listings and summary statistics and statistical analyses will be performed for subjects 
included in the relevant analysis populations (Safety/FAS/PPS/PK/Immunogenicity). Summary 
statistics and statistical analyses will be based on protocol defined nominal visit/timepoint. The 
data collected at the unscheduled visit/timepoint will be excluded from by-visit summary 
statistics and statistical analyses, but will be displayed in the data listings. 
The following conventions will be applied to present the analyses results, unless otherwise 
specified.
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
Descriptive statistics: 
–
For continuous data (study drug exposure and compliance, clinical laboratory data, vital 
signs, ECGs, etc.): 

n, mean, standard deviation, median, minimum, and maximum. 
–
For categorical data:

frequency counts and percentages. 
–
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. Percentages will be 
reported to 1 decimal place. For the calculation of summary statistics and statistical 
analysis, unrounded data will be used.
–
Where appropriate, variables will be summarized descriptively by treatment, visit, and 
timepoint. 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.
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) Analysis Data Model Version 2.1, and CDISC ADaM 
Implementation Guide Version 1.2. Pinnacle 21 Version 2.1.0 or higher will be utilized to ensure 
compliance with CDISC standards.
6.1.1
Handling of Treatment Misallocations
For all efficacy endpoints, subjects will be analyzed as randomized. For all safety endpoints, 
subjects will be analyzed as treated. 
6.1.2
Analysis Approach for Continuous Variables
The longitudinal continuous endpoints will be analyzed using MMRM as observed. This 
MMRM model will include treatment, sequence, period, timepoint, treatment-by-timepoint 
interaction and treatment-by-timepoint-by-period interaction as fixed effects, and subject-within-
sequence as a random effect. Covariance structure may be selected from: Autoregressive(1), 
Compound Symmetry, Unstructured, and Toeplitz. A model with each covariance structure will 
be fit, the models which converge will be compared using AICC. 
 =  + 2( + 2)( + 3)
 − −3
,
Where T is the number of observations and k is the number of predictors. 
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Point estimates, the associated 95% CIs and nominal p-values for treatment difference between 
TAK-951 and placebo will be presented at 0, 1, 2, 4, 8, 12, 24 hours postdose for peak nausea 
VRS score, and at 1, 2, 4, 8, 12, 24 hours postdose for change in nausea VRS score.
If the above MMRM model does not converge the endpoints will be analyzed using matched 
pairs t-tests. Multiple imputation for missing data will be used with the matched pairs t-test.
6.1.3
Analysis Approach for Binary Variables
The binary secondary efficacy endpoints will be summarized by treatment groups as observed. 
Treatment difference between TAK-951 and placebo at each scheduled timepoint will be 
estimated and the associated 95% CI will be constructed using normal approximation. These 
binary efficacy endpoints will be analyzed using a nonlinear mixed effects model with repeated 
measures (NMMRM) with treatment, sequence, period, timepoint, treatment-by-timepoint 
interaction, and treatment-by-timepoint-by-period interaction as fixed effects and subject-within-
sequence as a random effect based on the observed data as the main analysis method. The odds 
ratio between TAK-951 and placebo at each scheduled timepoint (i.e., 2, 4, 8, 12, and 24 hours 
postdose), the associated 95% CI and nominal p-value obtained from the nonlinear mixed effects 
model will be presented.
If the above NMMRM model fails to converge, binary efficacy endpoints will be analyzed using 
McNemar’s test, where subjects who have missing information to determine endpoint status will 
be considered as treatment failures. Count, percentage, treatment difference and p-value will be 
reported in this instance. 
6.1.4
Analysis Approach for Time-to-Event Variables
The time-to-event endpoints (time from dose to first emetic event) will be summarized by 
treatment groups. Subjects without documented events will be censored at the last visit. Kaplan-
Meier (KM) estimates and KM plots for appropriate endpoints will be provided.
6.2
Disposition of Subjects
Disposition of all randomized subjects (denominator) will be tabulated (count and percent). The 
summaries of disposition will be presented by treatment arm.
Disposition of all randomized subjects will be tabulated for each part of the study:

Subjects who were randomized but not treated, if applicable;

Subjects who completed the study investigational products;

Subjects who prematurely discontinued or withdrew study investigational products;

Subjects who completed all planned study visits;
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. Reasons for discontinuation or withdrawal include pre-treatment 
even, adverse event, LFT abnormalities, lost to follow-up, pregnancy, protocol deviation, study 
terminated by sponsor, voluntary withdrawal by subject, subject identified with COVID-19 
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infection, and Other. The date of first dose, date of last dose, number of dose received, and the 
reason for premature discontinuation of study drug/study visit will be presented for each subject 
in listings.
6.3
Demographic and Other Baseline Characteristics
6.3.1
Demographics and Baseline Characteristics
Descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum) will be generated for continuous demographic variables and baseline characteristics 
variables (eg, age, height, weight, and body mass index (BMI)) for placebo group and TAK-951. 
The number and percentage of subjects in each class of the categorical demographic variables 
and baseline characteristics variables (eg, gender, ethnicity, race) will be tabulated. Individual 
subject demographic and baseline characteristics data will be listed.
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI = kg/m2). 
The values should be reported to 1 decimal place by rounding.
6.3.2
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 24 or higher) coding system. 
During the screening period and prior to randomizarion, 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.
6.4
Medication History and Concomitant Medications 
Medication history includes all medications, other than study treatment, which was stopped at or 
prior to the first dose of study treatment. Only medications taken 6 months prior to study entry 
(ICF signing) will be included. Concomitant medication includes all medication, other than study 
treatment, which was started after the first dose of study treatment, through the end of the safety 
follow-up period. 
Medication history and concomitant medication will be coded using the World Health 
Organization Drug Dictionary (WHODrug, March, 2020 or higher) coding system.
The summary of concomitant medication will include the number and percentage of subjects by 
preferred term within each Anatomical Therapeutic Chemical (ATC) class level 2 by treatment 
arm using safety analysis set. The summary table will be presented with ATC class sorted in 
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alphabetical order and preferred term sorted in decreasing frequency based on the total number 
of subjects. A subject will be counted only once within a given ATC class and within a given 
preferred term, even if he/she received the same concomitant medication at different times.
All medication history and concomitant medication data will be provided in by-subject listings
using safety analysis set. 
6.5
Efficacy Analysis
The efficacy analyses will be conducted using the FAS. Sensitivity analyses based on PPAS will 
be performed for selected secondary efficacy endpoints (eg, data collected via ePRO diary, 
eObsRO diary). Selected secondary efficacy endpoints will be defined in a subsequent version of 
the SAP. Nominal p-values will be presented when appropriate. The efficacy data within the first 
30 minutes immediately following TAK-951/placebo administration will be excluded from the 
efficacy analysis as the dosing window allows for study drug/placebo to be given up to 1 hour 
into the emetic phase where subjects may already be experiencing severe, repeated bouts of 
emesis.
In addition to this SAP, a separate psychometric analysis plan will be developed to detail the 
COA evaluation methods of the COA endpoints. 
6.5.1
Secondary Endpoint(s) Analysis
6.5.1.1
Derivation of Endpoint(s)
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Endpoint
Definition
Total response (Yes/No) by ePRO and eObsRO
No emesis, no nausea (verbal rating scale [VRS] 
“none”) and no need for rescue therapy before each 
timepoint (by electronic reported patient-outcomes 
[ePRO and eObsRO]). 
Both ePRO and eObsRO must confirm the definition. 
If there is any disagreement or if either the ePRO or 
eObsRO are missing, then the value will be “No”.
Absence of emesis (Yes/No) by ePRO and eObsRO
No emesis and no need for rescue medication before 
each timepoint (ePRO and eObsRO]). 
Both ePRO and eObsRO must confirm the definition. 
If there is any disagreement or if either the ePRO or 
eObsRO are missing, then the value will be “No”.
Absence of significant nausea (Yes/No)
VRS of “none” or “mild” and no need for rescue 
medication before the evaluation timepoint (ePRO).
Peak nausea verbal rating scale (VRS) score at 0, 1, 2 
hours in all subjects and 4, 8, 12, 24 hours postdose 
without receiving rescue medication before the 
evaluation timepoint (ePRO). Data will also be 
collected at 3, 5, 6, and 7 hours postdose as able
Nausea has a lead in question of: 
“Did you experience nausea yes/no?”
If the response to this is “No”, then the subject will be 
listed as “none” for the VRS. If the subject responded 
“Yes”: 
Nausea (defined as the desire to vomit without the 
presence of expulsive muscular movements) will be 
scored using a self-reported, 4-point VRS of “none”, 
“mild”, “moderate” or “severe.” Significant nausea is 
defined as a VRS ≥”moderate”. The presence and 
severity of subject-reported nausea will be recorded in 
the ePRO and/or reported by the subject to the HCP 
and recorded in the eObsRO. The VRS scores for 
subjects after receiving rescue medication before the 
evaluation timepoint (ePRO) will be considered as 
missing data.
Data collected at 3, 5, 6, and 7 hours postdose will be 
included in the summary statistics and data listings but 
excluded from the statistical modeling.
Change in nausea VRS score at 1 and 2 hours in all 
subjects and 4, 8, 12, 24 hours postdose as compared 
with predose score without receiving rescue medication 
before the evaluation timepoint.
Value at given time (1,2,4,8,12,24) – predose value. 
The VRS scores for subjects after receiving rescue 
medication before the evaluation timepoint (ePRO) 
will be considered as missing data. Data collected at 3, 
5, 6, and 7 hours postdose will be included in the 
summary statistics and data listings but excluded from 
the statistical modeling.
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6.5.1.2
Main Analytical Approach
Binary secondary efficacy endpoints to be assessed at 2, 4, 8, 12 and 24 hours include:

Total response (Yes/No), defined as no emesis, no nausea (verbal rating scale [VRS] “none”) 
and no need for rescue therapy before each timepoint (by both ePRO and eObsRO inclusive). 

Absence of significant nausea (Yes/No), defined as VRS of “none” or “mild”, before each 
endpoint (ePRO).

Absence of emesis (Yes/No), defined as no emesis and no need for rescue medication before 
each timepoint (by both ePRO and eObsRO inclusive).
Binary Endpoints will be analyzed as described in Section 6.1.3. 
Longitudinal continuous secondary endpoints include: 

Peak nausea VRS score at 0, 1, 2 hours in all subjects and 4, 8, 12, 24 hours postdose in 
subjects who have not received rescue medication before the evaluation timepoint (ePRO).

Change in nausea VRS score at 1, 2 hours in all subjects and 4, 8, 12, 24 hours postdose as 
compared to predose score in subjects who have not received rescue medication before the 
evaluation timepoint

Status of subject’s ADA assessment (ie, ADA-negative or ADA positive, and low or high 
ADA titer).
Longitudinal continuous endpoints will be analyzed as described in Section 6.1.2. 
6.5.2
Exploratory Endpoint(s) Analysis
6.5.2.1
Derivation of Endpoint(s)
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Endpoint
Definition
Number of emeses by hour (eg 0-1h, 1-2h, 2-3h, etc)
Count of emeses (vomiting or retching) by hour (eg 
0-1h, 1-2h, 2-3h, etc)
Absence of emesis within 2 hours postdose (Yes/No)
Emeses (vomiting or retching) within 2 hours postdose. 
Absence of emesis within 4 hours postdose (Yes/No) in 
subjects who have not received rescue medication 
before the evaluation timepoint
Absence of emeses (vomiting or retching) within 4 
hours postdose.
Absence of emesis within 8 hours postdose (Yes/No) in 
subjects who have not received rescue medication 
before the evaluation timepoint
Absence of emeses (vomiting or retching) within 
8 hours postdose.
Time from dose to first emetic event (vomiting or 
retching), within each episode
Time of first emetic event – Start time of episode 
Total duration (min) of CVS episode
Time from study dose to subject-determined resolution 
of episode (i.e., back to baseline status) defined based 
on ePRO. 
Abdominal pain (peak score) at 0, 1, and 2 hours in all 
subjects and 4, 8, 12, and 24 hours postdose in subjects 
who have not received rescue medication before the 
evaluation timepoint
Max abdominal pain score at each timepoint (0, 1, and 
2 hours in all subjects and 4, 8, 12, and 24 hours 
postdose) in subjects who have not received rescue 
medication before the evaluation timepoint
Headache (peak score) at 0, 1, 2 hours in all subjects 
and 4, 8, 12, 24 hours postdose in subjects who have 
not received rescue medication before the evaluation 
timepoint
Max headache pain score at each timepoint (0, 1, and 2 
hours in all subjects and 4, 8, 12, and 24 hours 
postdose) in subjects who have not received rescue 
medication before the evaluation timepoint
Health-related quality of life (HRQOL) PROMIS-29 at 
baseline and in inter-episodic phase every 4 weeks
Score determined off of ePRO and 
Clinical Outcome Assessment Scales and 
Questionnaires v1.0.
Number of emergency department visits for CVS per 
CVS episode (Yes/No)
Count of emergency department visits per CVS 
episode defined below. 
CVS episode defined as: Onset of prodrome in 1 study 
episode to subject’s definition of resolution of that 
episode
Number of hospitalizations for CVS per CVS episode
Count of hospitalizations for CVS per CVS episode 
defined above. 
Rescue medication usage (Yes/No) per CVS episode
Rescue medication usage per CVS episode as defined 
above. 
Time from dosing to first use of rescue medication 
within each CVS episode
Date of Rescue Medication Administration - Date of 
First Dose + 1
CVS Episode defined above. 
Missed days of school/work due to CVS per CVS 
episode
Count of missed days of school/work due to CVS per 
CVS episode
Usability and feasibility of ePRO, eObsRO and audio 
monitor recording (embedded and exit interviews with 
patients and nurse practitioners)
This will be defined and the analysis will be described 
in a separate Biomarker Analysis Plan. 
Subject activity as a proxy for functional disability 
This will be defined and the analysis will be described 
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Endpoint
Definition
(
in a separate Biomarker Analysis Plan.
Change 
 from baseline 
(predose) to first emesis in those subjects who receive 
prodromal dosing (wearable event marker).
This will be defined and the analysis will be described 
in a separate Biomarker Analysis Plan.
6.5.2.2
Main Analytical Approach
The exploratory endpoints will be summarized descriptively by treatment groups as observed. 
Descriptive statistics for continuous endpoints will include number of subjects, number of 
observations, mean, standard deviation, median, minimum, and maximum.
Descriptive statistics for binary or categorical endpoints will include count and percentage. The 
time-to-event endpoints (time from dose to first emetic event), will be summarized by treatment 
groups. Subjects without documented events will be censored at the last visit. Kaplan-Meier 
(KM) estimates and KM plots for appropriate endpoints will be provided.
The analysis of exploratory biomarkers and audio markers will be described in a separate 
analysis plan and will be reported separately. 
6.6
Safety Analysis
Safety data will be summarized by treatment groups using the safety analysis set. No formal 
statistical testing or inference will be made. 
6.6.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 23.0 or higher and will be summarized by System Organ Class and Preferred Term by
treatment groups. Treatment-emergent adverse events will be summarized by treatment groups 
and. The number and percentage of subjects with treatment-emergent adverse events and SAEs 
will be summarized by MedDRA System Organ Class, High Level Term, and Preferred Term 
overall, by severity, and by relationship to study drug for each treatment group.
A treatment-emergent adverse event (TEAE) is defined as an AE that started or worsened after 
first dose of the study treatment and up to the date of the last follow-up visit. AEs with missing 
onset dates will be summarized with TEAEs regardless of toxicity grade and relationship to 
study medication.
The intensity of all AEs will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 5.0 or higher). AEs not listed by
the NCI CTCAE will be graded as displayed in Table 6.a.
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Table 6.a
NCI CTCAE
Grade
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
2
Moderate; minimal, local, or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living (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.
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;

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 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;

TEAEs of special interest (AESI) by SOC, HLT, and PT - number and percentage of 
subjects.
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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.

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, subject number and onset date of the adverse 
event. The listing will contain: subject identifier, age, sex, body weight, race, adverse event 
(preferred term and reported term), SOC, onset date, end date or whether the event was ongoing, 
duration, frequency, intensity, 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. 
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)
Orthostatic Hypotension
Orthostatic Hypotension (PT)
6.6.2
Clinical Laboratory Evaluation
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,
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
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 
Section 9.3 for details).
Individual subject clinical laboratory data will be listed by timepoint.
Blood samples for analysis of the Hematology, Serum Chemistry, Serum and Urine parameters 
are shown below:
6.6.2.1
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs] with absolute 
differential
6.6.2.2
Chemistry
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride and lipase
Creatinine
Glucose 
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total) if above the upper limit of normal, total 
bilirubin will be fractionated
Protein (total)
ALT: alanine aminotransferase; AST: aspartate aminotransferase
6.6.2.3
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrate
For Females only: hCG (for pregnancy)
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6.6.2.4
Diagnostic Screening
Other
HIV
Hepatitis screen (hepatitis B surface antigen, hepatitis C 
virus antibody)
FSH
βhCG (pregnancy) test
6.6.3
Vital Signs
Vital signs will include HR (bpm), respiratory rate, and systolic blood pressure and diastolic 
blood pressure in all parts of the study.
Absolute values and changes from baseline in vital signs parameters will be summarized 
descriptively for each treatment group. Individual vital sign results meeting the Takeda’s 
markedly abnormal criteria will be flagged and tabulated (see Section 9.4 for details).
6.6.4
ECG
ECG parameters (i.e., heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc 
interval (Fridericia’s)) will be summarized using descriptive statistics for baseline, postbaseline 
value, and change from baseline by treatment arm based on safety analysis set. The ECG 
parameters will be only summarized at the scheduled visits.
In addition, individual result for ECG parameters (heart rate, PR interval, QRS interval, and QTc 
interval) will be evaluated against the Takeda’s predefined markedly abnormal value (MAV) 
criteria (Criteria for Identification of Markedly Abnormal Values for the 12-Lead ECG 
Parameters). All postbaseline ECG data including scheduled and unscheduled measurements will 
be included in the MAV evaluation. For the ECG parameter of interest, the number and 
percentage of subjects with at least 1 postdose value meeting Takeda’s MAV criteria for ECG 
parameters will be presented by treatment arm based on safety analysis set. 
The investigator’s ECG interpretation (Normal, Abnormal but not clinically significant, or 
Abnormal and clinically significant, Not evaluable) will be summarized using a shift table as 
cross-tabulations (baseline versus each scheduled postbaseline visit) of numbers and percentage 
of subjects in each of appropriate categories by treatment arm based on safety analysis set.
All ECG data along with values meeting MAV criteria will be presented in the by-subject 
listings based on safety analysis set.
6.6.5
Other Safety Parameters
Physical examination findings will be presented in the data listings.
Depending on the prevalence of COVID-19 infections and illness in regions where the study is 
conducted, additional analysis may be performed to evaluate the impact of COVID on the safety 
of all participating subjects.
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6.6.6
Extent of 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. 
6.7
Immunogenicity Analysis
ADA positive is defined as subjects who have confirmed positive ADA status in at least 1 
postbaseline assessments. ADA negative is defined as subjects who do not have a confirmed 
positive ADA status in any postbaseline assessment.
For ADA positive only, high ADA titer is defined as subject who has at least 1 postbaseline 
ADA titer >16; low ADA titer is defined as subject whose postbaseline ADA titers are all ≤16.
Immunogenicity will be summarized using the number and percentage of subjects in the 
following categories: ADA status (ADA negative, ADA positive), ADA titer (low or high) at 
baseline and postbaseline visits by treatment arm based on immunogenicity analysis set. 
The summary of TEAE by PT and immunogenicity categories (ADA status (ADA negative, 
ADA positive), ADA titer (low or high)) and treatment arm based on immunogenicity analysis 
set may be provided to explore the relationship between immunogenicity status and safety, if 
deemed necessary.
The summary of PK parameters (including but not limited to Cmax, AUCs and CL/F where 
appropriate) by immunogenicity categories (ADA status (ADA negative, ADA positive), ADA 
titer (low or high)) and treatment arm based on immunogenicity analysis set may be provided to 
explore the relationship between immunogenicity status and PK, if deemed necessary.
All immunogenicity data will be provided in by-subject listings based on immunogenicity 
analysis set.
6.8
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
No formal noncompartmental PK analysis will be performed on concentration-time data. 
Summary statistics of plasma concentrations will be summarized using the PK set. Individual 
concentration data will be included in the listings using the PK set.
A population PK analysis may be conducted, and a more detailed description of these analyses 
may be given in a separate analysis plan. The results of these analyses will not be included in the 
clinical study report and may be a standalone report, if needed.
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6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
6.9.1
PRO Analysis
There will be both electronic patient reported outcomes (ePRO) and electronic observer-reported 
outcomes [eObsRO]). Both will be used to evaluate endpoints as described early. A separate 
psychometric analysis plan will detail the analysis and evaluation of ePRO and eObsRO. 
6.9.2
Health Care Utilization Analysis
Health-related quality of life (HRQOL) PROMIS-29 at baseline, monthly and at the end of every 
CVS episode. The data for this will be collected via the ePRO and the analysis and evaluation of 
this will be detailed in a separate psychometric analysis plan. 
6.10
Interim Analyses
An interim analysis (IA) may be conducted when approximately 50% of the total planned 
number of subjects have completed the study or withdrawn. Data for the selected secondary 
endpoints will be analyzed as part of the IA for internal decision making purposes. The sponsor 
personnel will not have access to the treatment assignment of individual subjects but only the 
aggregated IA results. Study site personnel and the study subjects will remain blinded to the 
treatment assignment for individual subjects and to the outcome of the IA until final database 
lock. Since this is a phase 1b study, the IA is intended to assist internal decision making and does 
not include a possibility to stop the study for efficacy or futility; there will not be alpha level 
adjustment for the final analysis.
Should the sponsor decide to conduct the IA, the study team would identify relevant TLFs for the 
purpose of the IA. Complete details related to the unblinding and analysis of interim data will be 
described in a subsequent version of SAP and data access management plan (DAMP). Further 
details will follow in a subsequent version of this analysis plan. 
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
An external independent DMC will conduct ongoing reviews of safety data. 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. 
7.0
REFERENCES
Burnham, K.P. and Anderson, D.R. (2002) Model Selection and Inference: A Practical 
Information-Theoretic Approach. 2nd Edition, Springer-Verlag, New York.
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Not Applicable 
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9.0
APPENDIX 
9.1
Data Handling Conventions 
9.1.1
Missing Data Handling 
9.1.1.1
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.
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.
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9.1.1.2
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.
9.1.1.3
Methods for Handling of Missing Efficacy Data
Missing data for longitudinal dichotomous efficacy endpoints will not be imputed, but handled 
using a nonlinear mixed effects model with repeated measures (NMMRM) assuming missing at 
random (MAR) mechanism. Other missing data handling method maybe explored such as 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 
MMRM assuming MAR. Other missing data handling method maybe explored such as the 
multiple imputation method.
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Missing data for time to event endpoints will not be imputed. 
Other missing data handling method may be explored.
9.1.2
Definition of Baseline 
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. 
Missing baseline values will not be imputed. 
9.1.3
Definition of Visit Windows 
Study visits do not have a set schedule but are based on nominal individual patient CVS 
episodes. Date and time of the Episode will be recorded. For purposes of time-to-event data visit 
day can be calculated as:
Date of event – Date of baseline + 1
9.1.4
Definition of Hour Window 
For each hour, the questionaire is initiated 1 minute after the hour and is available for 15 minute. 
It asks patients about their experience in the prior hour. 
The event marker and audio are available in real time. They will be cut off at the completion 
time of the questionaire. Then the next hour for these markers will continue. 
9.2
Analysis Software 
SAS 9.4 or greater
9.3
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. 
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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.
9.4
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
oC
<35.6
>37.7
oF
<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.
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9.5
Criteria for Identification of Markedly Abnormal Orthostatic Changes
Parameter
Criteria 
Orthostatic Hypotension
Orthostatic Tachycardia
Decrease in SBP ≥20 mm Hg or a decrease in DBP ≥10 mm Hg on 
standing 
Defined as an increase of >30 bpm or HR >120 bpm on standing
Note: Orthostatic measurement = standing vital measurement – supine vital measurement.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
090101d681189db4
TAK-951-1501 Statistical Analysis Plan 2021-09-09
Biostatistics Approval
10-Sep-2021 17:49 UTC
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