A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Rimegepant for Migraine Prevention in Japanese Subjects
Phase: PHASE3
Conditions: Migraine
Sponsor: Pfizer

Study BHV3000-309 (C4951021) Clinical Protocol, Version 5.0
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DRUG:
BHV-3000 (PF-07899801) (rimegepant)
STUDY NUMBER(S):
BHV3000-309 (C4951021)
PROTOCOL TITLE:
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety 
of Rimegepant for Migraine Prevention in Japanese 
Subjects
IND NUMBER:
N/A
EudraCT NUMBER:  
(if applicable)
N/A
ClinicalTrials.gov ID:
NCT05399485
SPONSOR:
Pfizer Inc.
66 Hudson Boulevard East New York, NY 10001
ORIGINAL PROTOCOL DATE:
04-Apr-2022
VERSION NUMBER:
5.0
VERSION DATE:
04-Aug-2023
BRIEF TITLE:
Efficacy and Safety Study of Rimegepant for 
Migraine Prevention in Japanese Subjects
This amendment incorporates all revisions to date, including amendments made at the request of 
country health authorities and IRBs/ECs and any protocol administrative change letter(s).
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment Version 5.0 (04 August 2023)
Overall Rationale for the Amendment: Change in sponsorship from Biohaven to Pfizer 
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Referenced study number 
BHV3000-309 to C4951021 and 
compound name BHV-3000 to 
PF-07899801 to reflect 
identification changes by sponsor.
Reflects change in sponsorship 
protocol and compound 
identification numbers.
Headers
Title page
1.1 Background
Changed sponsor name.
Reflects transfer of sponsorship 
from Biohaven Pharmaceuticals 
Holding Company Limited to 
Pfizer Inc.
Throughout the document
Added exclusion criterion for 
involvement in the conduct of the 
clinical trial by staff or family 
members.
Aligned with Pfizer protocol 
template.
5.3  Exclusion Criteria #7i
Allowed dose of aspirin up to 100 
mg daily for cardiovascular 
prophylaxis.
Aligned with ex-US dosing for 
low dose aspirin prophylaxis.
5.4 Prohibited and Restricted 
Concomitant Medications and 
Devices #22
Removed tacrolimus from the 
Strong CYP3A4 inhibitors list. 
Removed grapefruit juice from the 
Moderate CYP3A4 inhibitors list.
Aligned with nonclinical and 
clinical drug to drug interaction 
(DDI) information available on 
rimegepant.
16.1 APPENDIX 1 – Inhibitors 
and Inducers of CYP3A4 and 
Inhibitors of P-glycoprotein (Not 
all-inclusive) 
Changed the term Botox® to 
botulinum toxin injections.
Added broader drug class term.
5.5 Prophylactic and Rescue 
Medications
16.3 APPENDIX 3 – Categories of 
Migraine Prevention Medications
Changed term non-migraine to 
non-headache.
Clarified to include broader 
definition of headache which 
includes non-migraine and 
migraine headache.
5.4. Prohibited and Restricted 
Concomitant Medications #9
Updated potential drug-induced 
liver injury (DILI) cases 
identification and management.
Updated the requirement of 
laboratory testing accordingly.
Aligned with  Pfizer protocol 
template and the latest exclusion 
criteria.
6.2.4.1. Safety Laboratory Testing
8.4 Potential Drug Induced Liver 
Injury (DILI)
Clarified the requirement on the 
use of menstrual period paper log.
Clarified that menstrual period 
paper log is required only for 
women of childbearing potential 
(WOCBP).
4.3. Schedule of Assessments
Added appendix for ECG Findings 
of Potential Clinical Concern.
Aligned with Pfizer protocol 
template.
16.4. APPENDIX 4 – ECG 
Findings of Potential Clinical 
Concern
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Clarified definition of Sponsor's 
Medically Qualified Individual.
Aligned with Pfizer protocol 
template.
10.7. Sponsor’s Medically 
Qualified Individual
Non-substantial Modification(s)
Clarified the instruction for 
re-screening.
Clarified in accordance with the 
Dear Investigator Letter dated 
17May2023.
4.3.1.1 Screening Visit
4.3.1.2 Pre-randomization 
Evaluation Visit
Updated Serious Adverse Event 
(SAE) reporting destination and 
electronic reporting system 
administrative changes and 
clarifications.
Incorporation of non-substantial 
changes described in previous 
PACL dated 28Apr2023.
8.1.2 Collection and Reporting 
Serious Adverse Events
8.5.1. Exposure During Pregnancy
Updated a summary of the clinical 
data.
Aligned with the most current 
Investigator Brochure.
1.3. Product Development 
Background
Added benefit risk assessment.
Aligned with Pfizer protocol 
template.
1.4 Benefit Risk Assessment
Clarified definition of analysis 
sets/Added analysis sets.
Aligned with Statistical Analysis 
Plan.
9.2 Analysis Set
Clarified/corrected statistical 
methods.
Provided updates, corrections or 
clarifications. Aligned with
Statistical Analysis Plan.
9.1 Sample size
9.3.1 Primary Endpoint(s)
9.3.2 Secondary Endpoint(s)
9.3.3 Multiplicity Correction
9.3.4. Analysis of Safety
Clarified schedule of analyses.
Details on the schedule of analyses 
were added.
9.4 Schedule of Analyses
Updated text for Data Protection.
Aligned with Pfizer protocol 
template.
15. DATA PROTECTION
Added compliance aim for 
investigational product (IP) of 
80%.
Defined compliance for clarity.
7.4 Treatment Compliance
Updated study summary 
(Synopsis).
Aligned with Pfizer protocol 
template.
Study summary (Synopsis)
Removed Clinical Protocol 
Approval Form.
Aligned with Pfizer protocol 
template.
Clinical Protocol Approval Form
Removed PI declaration page.
Aligned with Pfizer protocol 
template.
Confidentiality and Investigator 
Statement
Removed Phase I study exception. 
Removed statement regarding 
Principal Investigator and the 
Sponsor’s representative 
signatory. Added Sponsor’s 
regulatory and ethics 
responsibilities.
Aligned with Pfizer protocol 
template.
10.1 Good Clinical Practice
Added Pfizer standard text for 
Dissemination of Clinical Study 
Data.
Aligned with Pfizer protocol 
template.
10.6 Dissemination of Clinical 
Study Data
Updated Section 8.3. Overdose. 
Overdose is reportable to Pfizer 
Safety only when associated with 
an SAE.
8.3. Overdose
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Updated the publication policy.
Updated in alignment with the 
change in sponsorship.
13. Publications Policy
Added adverse event (AE)
information on lack of efficacy 
and medication errors.
Aligned with Pfizer protocol 
template.
8.6 Lack of Efficacy
8.7 Medication Errors
Added Pfizer standard safety 
language for environmental 
exposure, exposure during 
pregnancy, exposure during 
breastfeeding, occupational 
exposure.
Aligned with Pfizer protocol 
template.
8.5 Environmental Exposure, 
Exposure During Pregnancy, or
Breastfeeding and Occupational 
Exposure
Moved prior Protocol Amendment 
Summary of Changes to 
Appendix.
Editorial.
16.5 APPENDIX 5 – Protocol 
Amendment History
Updated List of abbreviations.
Editorial.
List of Abbreviations
Removed Section 7.1.2 
Concomitant Therapy.
Editorial changes
7.1.2 Concomitant Therapy
Removed notified IRB/IEC within 
5 days.
Amended to allow for immediate 
action to be implemented.
12. AMENDMENTS
Corrected inconsistencies and
typographical errors throughout
the protocol.
Corrections to provide clarity and 
consistency throughout the 
protocol. 
Applicable sections of the protocol
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STUDY SUMMARY (SYNOPSIS)
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Rimegepant for Migraine Prevention in Japanese Subjects
Brief Title: Efficacy and Safety Study of Rimegepant for Migraine Prevention in Japanese 
Subjects
Regulatory Agency Identification Number(s):
US IND Number:
NA
EudraCT Number:
NA
ClinicalTrials.gov ID:
NCT05399485
Pediatric Investigational Plan Number:
NA
Protocol Number: 
BHV3000-309 (C4951021) Version 5.0 
Phase:
3
Rationale:
Rimegepant is being developed for the treatment of migraine. Effectiveness for the acute 
treatment of migraine was initially demonstrated in a Phase 2b double-blind, randomized, 
placebo-controlled, dose-ranging study where rimegepant at 75 mg showed efficacy on all 
4 traditional endpoints: pain, nausea, photophobia and phonophobia. Efficacy was confirmed in 
3 pivotal Phase 3 trials using the current registrational co-primary endpoints of Pain Freedom 
and Freedom from Most Bothersome Symptom at 2 hours after dosing. 
Additionally, in a double-blind placebo-controlled study rimegepant at a dose of 75 mg dosed 
every other day (EOD) demonstrated superiority to placebo on the primary endpoint of mean 
change from the Observation Period (OP) in the number of migraine days per month on 
treatment in the last month (Weeks 9 to 12) of the Double-blind Treatment Phase. 
This study is being conducted to evaluate the efficacy, safety, and tolerability of rimegepant in 
Japanese subjects for the prevention of migraine.
Primary Objectives:
To compare the efficacy of rimegepant relative to placebo as a preventive treatment for migraine.
Secondary Objectives:

To compare the efficacy of rimegepant to placebo on the following endpoints:

Proportion of the subjects that have 50% reduction from baseline in the number of 
moderate to severe migraine days per month in the last 4 weeks of the Double-blind 
Treatment Phase
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
The mean reduction from baseline in the number of migraine days per month over the 
entire course of the Double-blind Treatment Phase.

The mean reduction from baseline in the number of migraine days per month in the first 
4 weeks of the Double-blind Treatment Phase.

The mean number of acute migraine-specific medication (i.e., triptans and ergotamine) 
days per month in the last 4 weeks of the Double-blind Treatment Phase.

To compare the mean change from baseline in the Migraine-Specific Quality-of-Life 
Questionnaire v 2.1 (MSQoL v2.1) role function - restrictive domain score at Week 12 of the 
Double-blind Treatment Phase between rimegepant and placebo.

To compare the mean change from baseline in the Migraine Disability Assessment (MIDAS) 
total score at Week 12 of the Double-blind Treatment Phase between rimegepant and 
placebo.

To compare the mean change from baseline in the EuroQol 5 dimensions 5-level
(EQ-5D-5L) visual analog scale (VAS) score at Week 12 of the Double-blind Treatment 
Phase between rimegepant and placebo.

To evaluate the frequencies of AEs by intensity, SAEs, AEs leading to study drug 
discontinuation, and grade 3 to 4 laboratory test abnormalities in subjects treated with 
rimegepant during the Double-blind Treatment and Open-label Extension Phases.

To evaluate the frequency of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 × upper limit of normal (ULN) concurrent with total bilirubin (T bili) >2 × ULN in 
subjects treated with rimegepant during the Double-blind Treatment and Open-label 
Extension Phases.

To evaluate the frequencies of hepatic-related AEs and hepatic-related AEs leading to study 
drug discontinuation in subjects treated with rimegepant during the Double-blind Treatment 
and Open-label Extension Phases.
Primary Endpoint:
Mean change from baseline in the number of migraine days per month in the last 4 weeks 
(Weeks 9 to 12) of the Double-blind Treatment Phase.
Secondary Endpoints:
1. Proportion of subjects with ≥50% reduction from baseline in the number of moderate to 
severe migraine days per month in the last 4 weeks (Weeks 9 to 12) of the Double-blind 
Treatment Phase.
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2. Mean change from baseline in the number of migraine days per month over the entire 
Double-blind Treatment Phase (Weeks 1 to 12).
3. Mean change from baseline in the number of migraine days per month in the first 4 weeks 
(Weeks 1 through 4) of the Double-blind Treatment Phase.
4. Mean number of acute migraine-specific medication days per month in the last 4 weeks 
(Weeks 9 to 12) of the Double-blind Treatment Phase. Acute migraine-specific 
medications are triptans and ergotamine. 
5. Mean change from baseline in the MSQoL v2.1 role function - restrictive domain score at 
Week 12 of the Double-blind Treatment Phase.
6. Mean change from baseline in the MIDAS total score at Week 12 of the Double-blind 
Treatment Phase.
7. Mean change from baseline in the EQ-5D-5L VAS score at Week 12 of the Double-blind 
Treatment Phase.
8. Number and percentage of subjects with AEs by intensity, SAEs, AEs leading to study 
drug discontinuation and grade 3 to 4 laboratory test abnormalities on treatment during the 
Double-blind Treatment and Open-label Extension Phases.
9. Number and percentage of subjects with AST or ALT elevations > 3 x ULN concurrent 
(i.e., on the same laboratory collection date) with T bili > 2 x ULN on treatment during the 
Double-blind Treatment and Open-label Extension Phases. 
10. Number and percentage of subjects with hepatic-related AEs and hepatic-related AEs leading 
to study drug discontinuation on treatment during the Double-blind Treatment and Open-
label Extension Phases.
Overall Design:
This is a multicenter, randomized, double-blind, placebo-controlled bridging study to assess the 
efficacy and safety of rimegepant in migraine prevention in Japanese subjects with an Open-label 
Extension Phase.
The study will randomize approximately 490 subjects in a 1:1 ratio to the rimegepant or placebo 
treatment groups. The randomization will be stratified by the use of prophylactic migraine 
medications (yes or no).
The Screening Phase includes a Screening Visit and a 28-day OP. Upon completion of the 
Screening Visit, subjects will be provided an electronic diary (eDiary) to document migraine 
occurrence, migraine pain features and associated symptoms, and use of acute migraine 
medication on each day of the 28-day OP. Subjects will record the standard of care migraine 
treatment received on a paper diary. For subjects to be eligible for the study, they must report 
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having had 4 to 18 migraine attacks of moderate to severe intensity per 4-week period within the 
12 weeks prior to the Screening Visit, and at least 4 migraine days and no more than 18 headache 
days during the 28-day OP. After completing the 28-day OP, the subject will return to the 
clinical with both diaries for the Baseline Visit.
At the Baseline Visit, eligibility for continued participation in the study will be assessed before 
randomization occurs and before study drug is dispensed. Subjects will be instructed that they 
must take 1 orally disintegrating tablet (ODT) of blinded study drug (rimegepant 75 mg or 
placebo) every other calendar day. If subjects have a migraine attack during the Double-blind 
Treatment Phase, if needed, they may treat the migraine attack with their standard of care 
medication and continue to take study drug on their regular schedule (scheduled dosing days 
only). 
At the completion of the 12-week Double-blind Treatment Phase, subjects may be entered into 
the 40-week Open-label Extension Phase following laboratory results within acceptable ranges. 
During the Open-label Extension Phase, subjects will be instructed that they must take 
1 rimegepant 75 mg every other calendar day. If subjects have a migraine on a day that they are 
not scheduled to dose with rimegepant, they may take 1 rimegepant 75 mg on that calendar day 
to treat a migraine. Therefore, during the Open-label Extension Phase, subjects can take a 
maximum of 1 rimegepant 75 mg ODT per calendar day up to 40 weeks.
Subjects are required to record their migraine occurrence, migraine pain features and associated 
symptoms, and use of acute migraine medication  in the eDiary. Subjects are also required to 
record any rescue medication taken on a paper diary and WOCBP will record their menstrual 
period information on a paper log. 
At select study visits, subjects will complete or will be administered the Migraine-Specific 
Quality-of-Life Questionnaire v 2.1 (MSQoL v2.1), the Migraine Disability Assessment 
(MIDAS), EQ-5D-5L and the Columbia-Suicide Severity Rating Scale (C-SSRS).
Additional assessments and visit schedule are outlined in the procedural table in Section 4.3.
Study visits will occur at Screening (Enrollment), Baseline (Randomization), Week 2, Week 4, 
Week 8, and Week 12. At the completion of the 12-week Double-blind Treatment Phase, 
subjects may be entered into the 40-week Open-label Extension Phase following laboratory tests 
within normal ranges. Visits occur at Week 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52/ End of 
Treatment (EOT). Subjects will return to the study site at the end of Week 52 (+/-3 days) for the 
EOT Visit. Any subject who discontinues early, at any time during the study, will return to the 
study site for the EOT Visit. There is a Follow-up Visit 14 days (+/-2 days) after the EOT Visit. 
Subjects who do not complete the Double-blind Treatment Phase and/or do not enter or complete 
the Open-label Extension Phase should complete the EOT and the Follow-up Week 2 Visits.
To closely monitor for potential drug induced liver injury, guidance on reporting potential DILI 
events is provided in the protocol. Laboratory results that meet predefined liver function test 
(LFT) abnormality criteria as potential DILI events should be reported as a SAE. See Section 8.4
Potential Drug Induced Liver Injury (DILI).
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Number of Subjects:
Approximately 1064 subjects will be screened to randomize up to approximately 490 subjects 
(245 subjects to each of the rimegepant or placebo groups). It is estimated that approximately 
400 subjects will be entered into the Open-label Extension Phase.
Study Population:
The study will recruit male and female subjects, 18 years of age or older with at least a 1-year 
history of migraine (with or without aura) consistent with a diagnosis according to the 
International Classification of Headache Disorders, 3rd edition. Per their own report, subjects 
must have migraine onset prior to age 50, migraine attacks that last 4 to 72 hours (if not treated) 
and have had, 4-18 migraine attacks of moderate to severe intensity per 4 week period within 
the 12 weeks prior to the Screening Visit.
Statistical Methods:
The study will randomize roughly 245 subjects per treatment arm to obtain roughly 225 
evaluable subjects per treatment arm. With a sample size of roughly 490 subjects randomized, 
and 245 subjects per group, we expect roughly 225 evaluable subjects per group in the double-
blind treatment migraine analysis set. Assuming rimegepant provides roughly a 1 day advantage 
over placebo on the primary endpoint, and a common standard deviation of 3.75 days, then the 
study will have roughly 80% power on the primary endpoint at a 2-sided alpha level of 0.05.
The primary endpoint, mean change from OP in the number of migraine days per month in the 
last 4 weeks (Weeks 9 to 12) of the DBP phase will be assessed using a linear mixed effects 
model with repeated measures.
The proportion of subjects with 50% reduction from baseline in the number of moderate or 
severe migraine days per month in the last 4 weeks (Weeks 9 to 12) of the Double-blind 
Treatment Phase will be analyzed using a Mantel-Haenszel risk estimation with stratification by 
randomization stratum.
The mean change from baseline in the number of migraine days per month over the entire 
Double-blind Treatment Phase (Weeks 1 to 12) will be assessed with the same model used for 
the primary endpoint. 
The mean change from baseline in the number of migraine days per month in the first 4 weeks 
(Weeks 1 to 4) of the Double-blind Treatment Phase will be assessed with the same model used 
for the primary endpoint.
The mean number of acute migraine-specific medication days per month in the last 4 weeks 
(Weeks 9 to 12) of Double-blind Treatment Phase will be assessed using a linear mixed effects 
model with repeated measures.
The mean changes from baseline in MSQoL role function - restrictive domain score, MIDAS 
total score, and EQ-5D-5L VAS score at Week 12 will be assessed using linear models.
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Safety endpoints will be assessed descriptively.
Ethical Considerations: 
Broad and sustained efficacy of rimegepant 75 mg was demonstrated in 3 previously completed 
Phase 3 studies (BHV3000-301, BHV3000-302 and BHV3000-303). Statistically significant 
efficacy was demonstrated on the co-primary endpoints of freedom from pain, and freedom from 
most bothersome symptom at 2 hours post-dose. Also, in all 3 studies, significant results were 
achieved on photophobia freedom, phonophobia freedom and pain relief at 2 hours post-dose. 
Similar results were demonstrated in the BHV3000-310 study recently completed in China and 
Korea. In the Phase 2/3 placebo-controlled study (BHV3000-305) for the preventive treatment of 
migraine, rimegepant at a dose of 75 mg EOD demonstrated statistically significant superiority to 
placebo on the primary endpoint of change from the observation period in the mean number of 
migraine days per month on treatment in the last month of the double-blind treatment phase.
Review of all data available, including post-marketing information, nonclinical, clinical, and 
scientific literature data, demonstrates a favorable benefit-risk profile for the use of rimegepant 
in this study.
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STUDY SCHEMATIC
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES....................................................2
STUDY SUMMARY (SYNOPSIS)..........................................................................................5
STUDY SCHEMATIC ............................................................................................................11
TABLE OF CONTENTS.........................................................................................................12
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................16
LIST OF ABBREVIATIONS..................................................................................................17
1. INTRODUCTION AND RATIONALE..............................................................................21
1.1. Background .............................................................................................................21
1.2. CGRP ......................................................................................................................21
1.3. Product Development Background .........................................................................22
1.4. Benefit Risk Assessment.........................................................................................22
1.5. Study Rationale .......................................................................................................24
1.5.1. Study Design Rationale ..............................................................................24
1.5.2. Dose Selection Rationale............................................................................25
1.5.3. Research Hypothesis...................................................................................25
2. STUDY OBJECTIVES........................................................................................................26
2.1. Primary Objective(s) ...............................................................................................26
2.2. Secondary Objective(s) ...........................................................................................26
2.3. Exploratory Objective(s).........................................................................................27
3. STUDY ENDPOINTS.........................................................................................................28
3.1. Primary Endpoint(s) ................................................................................................28
3.2. Secondary Endpoint(s) ............................................................................................28
3.3. Exploratory Endpoint(s)..........................................................................................29
3.4. Definition of Migraine Days ...................................................................................30
3.5. Definition of Headache Days ..................................................................................30
4. STUDY PLAN.....................................................................................................................31
4.1. Study Design and Duration .....................................................................................31
4.2. Study Schematic......................................................................................................32
4.3. Schedule of Assessments ........................................................................................33
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4.3.1. Observation Period .....................................................................................40
4.3.1.1. Screening Visit ..........................................................................40
4.3.1.2. Pre-randomization Evaluation Visit..........................................40
4.3.2. Randomized, Double-Blind Treatment Phase (12 weeks)..........................41
4.3.2.1. Baseline (Randomization) Visit ................................................42
4.3.2.2. Week 12 or EOT Visit...............................................................42
4.3.3. Open-label Extension Phase (40 weeks).....................................................42
4.3.3.1. Week 52 or EOT Visit...............................................................43
4.3.4. Follow-up Period ........................................................................................44
4.3.4.1. Follow-up Week 2 Visit ............................................................44
4.4. Post Study Access to Therapy (if applicable) .........................................................44
5. POPULATION ....................................................................................................................45
5.1. Number of Subjects.................................................................................................45
5.2. Inclusion Criteria.....................................................................................................45
5.3. Exclusion Criteria....................................................................................................46
5.4. Prohibited and Restricted Concomitant Medications..............................................50
5.5. Prophylactic and Rescue Medications.....................................................................52
5.6. Women of Childbearing Potential...........................................................................53
5.7. Other Restrictions and Precautions (if applicable)..................................................54
5.8. Deviation from Inclusion/Exclusion Criteria ..........................................................54
6. STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES........................56
6.1. Study Materials .......................................................................................................56
6.2. Safety Assessments .................................................................................................57
6.2.1. Vital Signs and Physical Measurements (Height and Weight)...................57
6.2.2. Electrocardiogram (ECG)...........................................................................57
6.2.3. Physical Exam ............................................................................................57
6.2.4. Laboratory Assessments.............................................................................57
6.2.4.1. Safety Laboratory Testing.........................................................58
6.2.4.2. Pregnancy Testing.....................................................................59
6.2.5. Columbia-Suicide Severity Rating Scale (C-SSRS)...................................59
6.3. Efficacy Assessments..............................................................................................59
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6.4. Other Assessments ..................................................................................................59
6.4.1. Migraine-Specific Quality-of-Life Questionnaire v 2.1.............................59
6.4.2. Migraine Disability Assessment (MIDAS) Questionnaire.........................60
6.4.3. EQ-5D-5L...................................................................................................60
6.5. Early Discontinuation from the Study.....................................................................60
6.5.1. Lost to Follow Up.......................................................................................61
7. STUDY DRUG MANAGEMENT......................................................................................62
7.1. Description of Study Drug ......................................................................................62
7.1.1. Investigational Product ...............................................................................62
7.1.2. Packaging, Shipment and Storage ..............................................................62
7.2. Dose and Administration.........................................................................................62
7.2.1. Method of Assigning Subject Identification...............................................62
7.2.2. Selection and Timing of Dose and Administration ....................................63
7.2.3. Dose Modifications.....................................................................................63
7.2.4. Dose Interruptions ......................................................................................63
7.3. Blinding and Unblinding.........................................................................................63
7.4. Treatment Compliance ............................................................................................64
7.5. Destruction and Return of Study Drug....................................................................65
8. ADVERSE EVENTS...........................................................................................................66
8.1. Serious Adverse Events...........................................................................................67
8.1.1. Definition of Serious Adverse Event (SAE)...............................................67
8.1.2. Collection and Reporting Serious Adverse Events.....................................69
8.2. Non-serious Adverse Events ...................................................................................70
8.2.1. Collection and Reporting of Non-Serious Adverse Events ........................70
8.2.2. Laboratory Test Abnormalities...................................................................70
8.3. Overdose..................................................................................................................70
8.4. Potential Drug Induced Liver Injury (DILI) ...........................................................71
8.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure..............................................................................................72
8.5.1. Exposure During Pregnancy.......................................................................72
8.5.2. Exposure During Breastfeeding..................................................................74
8.5.3. Occupational Exposure...............................................................................75
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8.6. Lack of Efficacy......................................................................................................75
8.7. Medication Errors....................................................................................................75
8.8. Adverse Events of Special Interest..........................................................................75
9. STATISTICS .......................................................................................................................76
9.1. Sample Size.............................................................................................................76
9.2. Analysis Set.............................................................................................................76
9.3. Statistical Methods ..................................................................................................77
9.3.1. Primary Endpoint(s)....................................................................................77
9.3.2. Secondary Endpoint(s)................................................................................77
9.3.3. Multiplicity Correction...............................................................................78
9.3.4. Analysis of Safety.......................................................................................78
9.4. Schedule of Analyses ..............................................................................................79
10. ETHICS AND RESPONSIBILITIES................................................................................80
10.1. Good Clinical Practice ..........................................................................................80
10.2. Data and Safety Monitoring Committee ...............................................................80
10.3. Institutional Review Board/Independent Ethics Committee.................................81
10.4. Informed Consent..................................................................................................81
10.5. Case Report Forms................................................................................................82
10.6. Dissemination of Clinical Study Data...................................................................82
10.6.1. Data sharing..............................................................................................83
10.7. Sponsor’s Medically Qualified Individual ............................................................83
11. RECORDS MANAGEMENT ...........................................................................................84
11.1. Source Documentation ..........................................................................................85
11.2. Study Files and Record Retention.........................................................................85
12. AMENDMENTS ...............................................................................................................86
13. PUBLICATIONS POLICY ...............................................................................................86
14. STUDY DISCONTINUATION ........................................................................................86
15. DATA PROTECTION.......................................................................................................86
16. APPENDICES ...................................................................................................................88
16.1. APPENDIX 1 – Inhibitors and Inducers of CYP3A4 and Inhibitors of P-
glycoprotein (Not all-inclusive) ................................................................................88
16.2. APPENDIX 2 – Definition of Migraine Days ......................................................90
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16.3. APPENDIX 3 – Categories of Migraine Prevention Medications........................92
16.4. APPENDIX 4 - ECG Findings of Potential Clinical Concern..............................93
16.5. APPENDIX 5 – Protocol Amendment History.....................................................95
17. REFERENCES ..................................................................................................................97
LIST OF TABLES
Table 1
Schedule of Assessments – Observation Period, Double-blind 
Treatment Phase........................................................................................33
Table 2
Schedule of Assessments – Open-label Treatment Phase, Follow-up 
Visits.........................................................................................................37
LIST OF FIGURES
Figure 1
Study Schematic .......................................................................................32
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LIST OF ABBREVIATIONS
ADHD
Attention-Deficit Hyperactivity Disorder
ACE
Angiotensin converting enzyme
AE
Adverse Event
ALT
Alanine Aminotransferase
ARB
Angiotensin receptor blocker
AST
Aspartate Aminotransferase
AV
Atrioventricular
BHV
Biohaven
bpm
beats per minute
BUN
Blood Urea Nitrogen
CGRP
Calcitonin Gene-Related Peptide
CI
Confidence interval
CK
Creatine kinase
COVID-19
Coronavirus Disease of 2019
CRF
Case Report Form
CRO
contract research organization
CRPS
Complex Regional Pain Syndrome
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
Clinical Trial
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trial Information System
CV
Cardiovascular
CYP
cytochrome P450
DAIDS
Division of AIDS
DDI
drug-drug interaction
DILI
Drug-Induced Liver Injury
DSM-V
Diagnostic and Statistical manual of Mental Disorders Fifth edition
DSU
Drug Safety Unit
EC
ethics committee
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ECC
emergency contact card
ECG
Electrocardiogram
EDB
Exposure During Breastfeeding
EDC
Electronic Data Capture
eDiary
Electronic diary
EDP
Exposure During Pregnancy
eGFR
Estimated glomerular filtration rate
EOD
Every Other Day
EOT
End of Treatment
EQ-5D-5L
EuroQol 5 dimensions 5-level
eTMF
electronic Trial Master File
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials (European 
Clinical Trials Database)
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
HbA1c
Hemoglobin A1c
HR
heart rate
HRT
hormone replacement therapy
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
identification
IEC
Independent Ethics Committee
IHS
International Headache Society
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
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IRB
Institutional Review Board
ISF
investigator site file
IWRS
Interactive Web Response System
kg
Kilogram
L
Liters
LBBB
left bundle branch block
LFT
Liver Function Test
LSLV
last subject last visit
mg
Milligram
MedDRA
Medical Dictionary for Regulatory Activities
MIDAS
Migraine Disability Assessment
MSQoL
Migraine-Specific Quality-of-Life Questionnaire 
min
Minute
mmHg
Millimeters Mercury
MQI
medically qualified individual
NSAID
Nonsteroidal Anti-inflammatory Drugs
ODT
Orally disintegrating tablets
OP
Observation period
PACL
Protocol Administrative Clarification Letter
PCD
primary completion date
PCP
Phencyclidine
P-gp
P-glycoprotein
PK
Pharmacokinetic
PRN
Pro re nata, as needed
PSSA
Pfizer SAE Submission Assistant
PT
prothrombin
PVC
premature ventricular contraction
QTc
Interval between Q-wave and T-wave in the cardiac cycle
QTcF
QTc corrected using Fridericia’s formula
QTL
Quality Tolerance Limits
SAE
Serious Adverse Event
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SAP
Statistical Analysis Plan
SE
Standard error
SOP
standard operating procedure
SRSD
Single Reference Safety Document
T bili
Total bilirubin
THC
Tetrahydrocannabinol
TMF
Trial Master File
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
VAS
Visual Analog Scale
WBC
White Blood Cell
WOCBP
Women of Childbearing Potential
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1. INTRODUCTION AND RATIONALE
1.1. Background
Migraine is a common and debilitating neurological disorder that affects approximately 8.4% of 
the adult population in Japan1. It is characterized by moderate-to-severe episodic unilateral 
pulsating headaches that last for 4 to 72 hours. Typical characteristics of the headache are 
unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine 
physical activity, and association with nausea and/or photophobia and phonophobia. 
BHV-3000 (PF-07899801) (Rimegepant) is a calcitonin gene-related peptide (CGRP) receptor 
antagonist in development for the acute treatment of migraine. The CGRP receptor is located 
within pain-signaling pathways, intracranial arteries and mast cells and its activation is thought 
to play a causal role in migraine pathophysiology. For example, research and clinical studies 
have shown: serum levels of CGRP are elevated during migraine attacks, infusion of intravenous 
CGRP produces persistent pain in migraine sufferers and non-migraine sufferers, and treatment 
with anti-migraine drugs normalize CGRP levels. Additionally, multiple clinical studies show 
that small molecule CGRP receptor antagonists, which inhibit the binding of endogenous CGRP 
to CGRP receptors, are effective in aborting migraine attacks. Treatment with a CGRP receptor 
antagonist is believed to relieve migraine through the possible mechanisms of 1) blocking 
neurogenic inflammation, 2) decreasing artery dilation, and 3) inhibiting pain transmission. This 
new approach to the treatment of migraine avoids the cardiovascular effects produced by active 
vasoconstriction associated with the current standard triptan therapy (non-selective 5-HT1B/1D 
agonists (e.g., sumatriptan [Imitrex™]).
1.2. CGRP
Rimegepant is a selective, high-affinity, orally administered, small molecule calcitonin gene-
related peptide (CGRP) receptor antagonist.
CGRP is an endogenous 37 amino acid peptide contained within pain-signaling nociceptive 
afferents, and is thought to play a causal role in migraine2,3. Multiple lines of clinical evidence 
point to a role for CGRP in migraine pathophysiology: 1) serum levels of CGRP are elevated 
during migraine4; 2) treatment with anti-migraine drugs returns CGRP levels to normal 
coincident with pain relief4,5; and 3) intravenous CGRP infusion produces lasting pain in non-
migraineurs and migraineurs3,6.
Rimegepant offers a novel therapeutic mechanism for the acute treatment of migraine with the 
potential to address important unmet needs (e.g., single-dose durable efficacy, efficacy without 
medication overuse headache, and no contraindications or warnings in patients with 
cardiovascular [CV] disease).
The CGRP receptor is located within pain-signaling pathways, intracranial arteries and mast cells 
and its activation is thought to play a causal role in migraine pathophysiology. For example, 
research and clinical studies have shown: serum levels of CGRP are elevated during migraine 
attacks, infusion of intravenous CGRP produces persistent pain in migraine sufferers and non-
migraine sufferers, and treatment with anti-migraine drugs normalize CGRP levels. Additionally, 
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multiple clinical studies show that small molecule CGRP receptor antagonists, which inhibit the 
binding of endogenous CGRP to CGRP receptors, are effective in aborting migraine attacks.
Treatment with a CGRP receptor antagonist is believed to relieve migraine through the following 
possible mechanisms:

Blocking Neurogenic Inflammation: Binding of CGRP receptor antagonists to CGRP 
receptors located on mast cells would inhibit inflammation caused by trigeminal nerve 
release of CGRP onto mast cells within the tough outer covering of the brain, or the 
meninges.

Decreasing Artery Dilation: By blocking the CGRP receptors located in smooth muscle 
cells within vessel walls, CGRP receptor antagonists would inhibit the pathologic dilation of 
intracranial arteries without the unwanted effect of active vasoconstriction.

Inhibiting Pain Transmission: Binding of CGRP receptor antagonists to CGRP receptors 
would suppress the transmission of pain by inhibiting the central relay of pain signals from 
the trigeminal nerve to the caudal trigeminal nucleus.
1.3. Product Development Background
Details of the clinical and preclinical studies are provided in the most current Investigator 
Brochure. A summary of the relevant data is presented below.
As of 26-Aug-2022, more than 8,900 unique subjects have participated in Phase 1 studies in 
healthy subjects or Phase 2 and 3 studies in subjects with migraine; of these, approximately 
6,036 unique subjects have received rimegepant at any dose. Overall, 1,857 unique subjects 
received rimegepant 75 mg in single dose studies: 1,771 unique subjects in the 3 pivotal Phase 3 
single-dose, placebo-controlled, acute treatment studies (i.e., BHV3000-3037, BHV3000-3028, 
and BHV3000-3019), and 86 subjects in the Phase 2b dose-ranging study CN17000310. Safety 
data are also available for the 2,471 subjects who received rimegepant 75 mg in the Phase 2/3 
multiple dose studies (BHV3000-20111 and BHV3000-30512). In the pivotal migraine 
prophylaxis study (BHV3000-305), the Open-label Extension Phase remains ongoing, and a total 
of 527 subjects received rimegepant 75 mg (EOD or EOD + PRN up to once daily for at least 6 
months, and 416 subjects received rimegepant for at least 1 year. In the supportive long-term 
safety study (BHV3000-201), a total of 1,154 subjects received rimegepant 75 mg for at least 6 
months, and 368 subjects received rimegepant for at least 1 year.
Rimegepant is generally safe and well tolerated in humans when given as single oral doses up to 
the maximum dose of 1500 mg and multiple oral doses up to the maximum daily dose of 600 mg 
for 14 days. 
1.4. Benefit Risk Assessment
Rimegepant is approved in the US, EU, and UK for the treatment of migraine in adults, including 
both acute treatment of migraine and preventive treatment of episodic migraine. Rimegepant 
appears to be generally safe and well tolerated in humans when given as single oral doses from 
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75 mg up to the maximum dose of 1,500 mg and multiple oral doses up to the maximum daily 
dose of 600 mg for 14 days. Rimegepant 75 mg represents an advancement in migraine 
therapeutics, providing the first CGRP antagonist to demonstrate benefit for both the acute 
treatment and prophylaxis of migraine. Dual action therapy for migraine with a single agent 
offers patients the potential for significant clinical advantages including: 1) a simplified 
medication regimen to treat migraine across the spectrum from acute episodes to the prevention 
of future attacks, which are two manifestations of the same condition; 2) avoiding polypharmacy 
with concurrent use of multiple medications each with their own side effects; 3) reducing the risk 
of drug-drug interactions; and 4) cost-effectiveness of a single medication that provides both 
acute and preventive therapy.
Broad and sustained efficacy of rimegepant 75 mg was demonstrated in 3 previously completed 
Phase 3 studies (BHV3000-301, BHV3000-302 and BHV3000-303). Statistically significant 
efficacy was demonstrated on the co-primary endpoints of freedom from pain, and freedom from 
most bothersome symptom at 2 hours post-dose. Also, in all 3 studies, significant results were 
achieved on photophobia freedom, phonophobia freedom and pain relief at 2 hours post-dose. 
Similar results were demonstrated in the BHV3000-310 study recently completed in China and 
Korea. In the Phase 2/3 placebo-controlled study (BHV3000-305) for the preventive treatment of 
migraine, rimegepant at a dose of 75 mg EOD demonstrated statistically significant superiority to 
placebo on the primary endpoint of change from the observation period in the mean number of 
migraine days per month on treatment in the last month of the double-blind treatment phase.
A multicenter open-label, long-term study (BHV3000-201) was conducted to evaluate the safety 
and tolerability of rimegepant 75 mg tablet taken as needed (up to 1 tablet per day upon onset of 
a migraine of mild, moderate, or severe intensity) for the acute treatment of migraine for up to 52 
weeks. This multiple-dose, long-term study of rimegepant 75 mg administered for up to 52 
weeks confirmed the favorable safety profile across a variety of safety endpoints, including AE 
assessments, clinical laboratory testing including LFTs, vital signs and electrocardiograms 
(ECGs). Safety data from the double-blind treatment and the open-label extension phases of the 
pivotal Phase 2/3, randomized, double-blind, placebo-controlled preventive treatment of 
migraine study (BHV3000-305) support a favorable safety profile of rimegepant 75 mg 
administered EOD for the preventive treatment of migraine. Rimegepant 75 mg administered 
EOD + PRN for up to 52 weeks in the open-label phase is well tolerated, with no new safety 
signals observed in the open-label-extension phase.
Across rimegepant clinical development program, low frequency of events of hypersensitivity 
(including urticaria, angioedema, anaphylactic reaction and rash) were observed. No AEs 
representing serious cutaneous manifestation of hypersensitivity (eg, Stevens-Johnson syndrome) 
were observed. 
Across the rimegepant clinical development program, no cases of Hy’s Law were identified, and 
there was no signal of DILI due to rimegepant when administered up to once daily PRN for up to 
52 weeks of treatment.
There are no adequate data on the developmental risk associated with the use of rimegepant in 
pregnant women. WOCBP must have a negative pregnancy test and WOCBP and fertile men 
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must use two acceptable methods of contraception to avoid pregnancy throughout the study in 
such a manner that the risk of pregnancy is minimized. Subjects undergo regular pregnancy 
testing throughout the duration of the study. Although no safety issues in clinical trials of 
rimegepant were observed, cardiovascular events, cerebrovascular events, hypertensive events, 
and serious gastrointestinal events associated with constipation are reviewed in each aggregate 
report per FDA request. None of these reviews have detected any safety signal associated with 
these events. Subjects are excluded if there is uncontrolled, unstable, or recently diagnosed 
cardiovascular disease or hypertension. Subjects are monitored through multiple safety 
endpoints, including AE assessments, clinical laboratory testing, vital signs and ECGs.
Review of all data available, including post-marketing information, nonclinical, clinical, and 
scientific literature data, demonstrates a favorable benefit-risk profile for the use of rimegepant 
in this study. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of rimegepant may be found in the Investigator’s Brochure, which is 
the single reference safety document (SRSD) for this study.
1.5. Study Rationale
The demonstrated efficacy of rimegepant in adults in the 3 pivotal Phase 3 registrational trials in 
the acute treatment of migraine and the safety profile observed to date in the Phase 2/3 
BHV3000-201 long-term open-label safety study with up to daily dosing for as long as 1 year 
suggest that rimegepant may have an important role in the treatment of migraine.
Additionally, the U.S. trial BHV3000-305, a Phase 2/3, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety in the preventive treatment of migraine, 
demonstrated efficacy of rimegepant in the preventing treatment of episodic migraine in adults.
The above package of studies supported the registration and approval of rimegepant in the US, 
UK and EU. for the acute treatment of migraine and for migraine prophylaxis. The purpose of 
the current study is to provide confirmatory evidence of the efficacy of rimegepant for migraine 
prophylaxis in Japanese subjects with migraine, thus permitting bridging to the results from the 
global rimegepant efficacy and safety program. 
1.5.1. Study Design Rationale
This is a 12-week multicenter, randomized, double-blind, placebo controlled evaluation of the 
safety and efficacy of rimegepant 75 mg ODT taken every other day for the prevention of 
migraine with a 40-week Open-label Extension Phase. Up to approximately 490 subjects will be 
randomized and assigned treatment in the Double-blind Treatment Phase; it is estimated that 
approximately 400 subjects will enter the Open-label Extension Phase. During the Double-blind 
Treatment Phase, subjects will be instructed that they must take 1 ODT of blinded study drug 
every other calendar day. If subjects have a migraine during the Double-blind Treatment Phase, 
if needed, they may treat the migraine with their standard of care medication and continue to take 
study medication on their regular schedule (scheduled dosing days only).
During the Open-label Extension Phase, subjects will be required to take 1 ODT of rimegepant 
every other calendar day. However, if subjects have a migraine on a day that they are not 
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scheduled to dose with rimegepant, they may take 1 ODT of rimegepant on that calendar day to 
treat the migraine. Dosing with more than 1 ODT of study medication per calendar day is not 
permitted. Therefore, subjects can take a maximum of 1 ODT of study drug per calendar day for 
the 40 weeks of the Open-label Extension Phase.
The study will randomize approximately 490 subjects and it is expected that approximately 400 
subjects will enter the Open-label Extension Phase. During the Double-blind Treatment Phase, 
the subjects will be randomized in a 1:1 ratio to the rimegepant or placebo treatment groups, 
stratified by current use of prophylactic migraine medications (yes or no).
1.5.2. Dose Selection Rationale
The Phase 2b dose-ranging study CN170003 established that rimegepant 75 mg is the minimum 
effective dose for the acute treatment of migraine. The 3 Phase 3 studies BHV3000-301, 
BHV3000-302, and BHV3000-303 confirmed this efficacy using the current registrational 
endpoints for acute treatment of migraine. Likewise, the adult prevention study, BHV3000-305, 
confirmed that 75 mg EOD is an effective dose for the preventive treatment of episodic migraine 
in adults. 
BHV3000-111 was a Phase 1, randomized, placebo-controlled, multiple-dose, double-blind 
study to evaluate and compare the PK and safety of rimegepant in healthy Caucasian and 
Japanese subjects. Rimegepant administered as multiple doses of 25 mg, 75 mg, and 150 mg is 
safe and well tolerated in healthy adult Caucasian and Japanese subjects. In addition, weight-
normalized PK parameters were comparable between Caucasian and Japanese subjects and no 
dose or dose frequency adjustment is required in Japanese patients.
Thus, the 75 mg EOD dose is hypothesized to be effective in Japanese patients for the prevention 
of episodic migraine. 
1.5.3. Research Hypothesis
Rimegepant is a safe and effective treatment for the prevention of migraine in Japanese subjects.
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2. STUDY OBJECTIVES
2.1. Primary Objective(s)
To compare the efficacy of rimegepant relative to placebo as a preventive treatment for migraine 
as measured by the mean reduction from baseline in the number of migraine days per month in 
the last 4 weeks of the Double-blind Treatment Phase (A month is defined as 4 weeks for the 
purpose of this protocol).
2.2. Secondary Objective(s)
1. To compare the efficacy of rimegepant to placebo on the proportion of the subjects that have 
50% reduction from baseline in the number of moderate to severe migraine days per month 
in the last 4 weeks of the Double-blind Treatment Phase.
2. To compare the efficacy of rimegepant to placebo on the mean reduction from baseline in the 
number of migraine days per month over the entire course of the Double-blind Treatment 
Phase.
3. To compare the efficacy of rimegepant to placebo on the mean reduction from baseline in the 
number of migraine days per month in the first 4 weeks of the Double-blind Treatment 
Phase.
4. To compare the efficacy of rimegepant to placebo on the mean number of acute migraine-
specific medication (i.e., triptans and ergotamine) days per month in the last 4 weeks of the 
Double-blind Treatment Phase.
5. To compare the mean change from baseline in the Migraine-Specific Quality-of-Life 
Questionnaire v 2.1 (MSQoL v2.1) role function - restrictive domain score at Week 12 of the 
Double-blind Treatment Phase between rimegepant and placebo.
6. To compare the mean change from baseline in the Migraine Disability Assessment (MIDAS) 
total score at Week 12 of the Double-blind Treatment Phase between rimegepant and 
placebo.
7. To compare the mean change from baseline in the EQ-5D-5L visual analog scale (VAS) 
score at Week 12 of the Double-blind Treatment Phase between rimegepant and placebo.
8. To evaluate the frequencies of AEs by intensity, SAEs, AEs leading to study drug 
discontinuation, and grade 3 to 4 laboratory test abnormalities in subjects treated with 
rimegepant during the Double-blind Treatment and Open-label Extension Phases.
9. To evaluate the frequency of ALT or AST >3 x ULN concurrent with T bili >2 x ULN in 
subjects treated with rimegepant during the Double-blind Treatment and Open-label 
Extension Phases.
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10. To evaluate the frequencies of hepatic-related AEs and hepatic-related AEs leading to study 
drug discontinuation in subjects treated with rimegepant during the Double-blind Treatment 
and Open-label Extension Phases.
2.3. Exploratory Objective(s)
1. To evaluate the efficacy of rimegepant to placebo on the mean reduction from baseline in the 
number of migraine days per month by pain intensity (total; moderate or severe) in each 
month and the entire course of the Double-blind Treatment Phase.
2. To evaluate the efficacy of rimegepant to placebo on the proportion of the subjects that have 
50% reduction, 75% reduction, and 100% reduction from baseline in the number of 
migraine days per month by pain intensity (total; moderate or severe) in each month and the 
entire course of the Double-blind Treatment Phase. 
3. To evaluate the efficacy of rimegepant to placebo on the mean reduction from baseline in the 
number of migraine days per week by pain intensity (total; moderate or severe) in each week 
of the first 4 weeks of the Double-blind Treatment Phase.
4. To evaluate the mean reduction in the number of migraine days per month by pain intensity 
(total; moderate or severe) in each month and the entire course of the Open-label Extension 
Phase.
5. To evaluate the proportion of the subjects that have 50% reduction, 75% reduction, and 
100% reduction from baseline in the number of migraine days per month by pain intensity 
(total; moderate or severe) in each month and the entire course of the Open-label Extension 
Phase.
6. To evaluate the efficacy of rimegepant to placebo on the mean number of acute migraine-
specific medication (i.e., triptans and ergotamine ) days per month and acute migraine 
medication days per month in each month and the entire course of the Double-blind 
Treatment Phase.
7. To evaluate the mean number of acute migraine-specific medication days per month and 
acute migraine medication days per month in each month and the entire course of the Open-
label Extension Phase.
8. To evaluate the mean changes from baseline in MSQoL domain scores, MIDAS scores, and 
EQ-5D-5L VAS score over time during the Double-blind Treatment and Open-label 
Extension Phases. 
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3. STUDY ENDPOINTS 
Migraine days per month, acute migraine-specific medication days per month, and acute 
migraine medication days per month are derived from eDiary data. For these endpoints, the 
Observation Period represents “baseline”.
AEs are determined from case report forms (CRFs).
MSQoL domain scores, MIDAS scores, and EQ-5D-5L VAS score are derived from eDiary data.
Grade 3 to 4 laboratory test abnormalities are determined from laboratory test values graded 
using standardized criteria. Laboratory tests are identified from CRFs and central laboratory data.
3.1. Primary Endpoint(s)
Mean change from baseline in the number of migraine days per month in the last 4 weeks 
(Weeks 9 to 12) of the Double-blind Treatment Phase.
3.2. Secondary Endpoint(s)
1. Proportion of subjects with 50% reduction from baseline in the number of moderate to 
severe migraine days per month in the last 4 weeks (Weeks 9 to 12) of the Double-blind 
Treatment Phase.
2. Mean change from baseline in the number of migraine days per month over the entire 
Double-blind Treatment Phase (Weeks 1 to 12).
3. Mean change from baseline in the number of migraine days per month in the first 4 weeks 
(Weeks 1 through 4) of the Double-blind Treatment Phase.
4. Mean number of acute migraine-specific medication days per month in the last 4 weeks 
(Weeks 9 to 12) of the Double-blind Treatment Phase. Acute migraine-specific medications 
are triptans and ergotamine. 
5. Mean change from baseline in the MSQoL v2.1 role function - restrictive domain score at 
Week 12 of the Double-blind Treatment Phase.
6. Mean change from baseline in the MIDAS total score at Week 12 of the Double-blind 
Treatment Phase.
7. Mean change from baseline in the EQ-5D-5L VAS score at Week 12 of the Double-blind 
Treatment Phase.
8. Number and percentage of subjects with AEs by intensity, SAEs, AEs leading to study drug 
discontinuation and grade 3 to 4 laboratory test abnormalities on treatment during the 
Double-blind Treatment and Open-label Extension Phases.
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9. Number and percentage of subjects with of AST or ALT elevations > 3 x ULN concurrent 
(i.e., on the same laboratory collection date) with T bili > 2 x ULN on treatment during the 
Double-blind Treatment and Open-label Extension Phases. 
10. Number and percentage of subjects with hepatic-related AEs and hepatic-related AEs leading 
to study drug discontinuation on treatment during the Double-blind Treatment and Open-
label Extension Phases.
3.3. Exploratory Endpoint(s)
1. Mean change from baseline in the number of migraine days per month by pain intensity 
(total; moderate or severe) in each month and the entire course of the Double-blind 
Treatment Phase.
2. Proportion of subjects with 50% reduction, 75% reduction, and 100% reduction from 
baseline in the number of migraine days per month by pain intensity (total; moderate or 
severe) in each month and the entire course of the Double-blind Treatment Phase. 
3. Mean change from baseline in the number of migraine days per week by pain intensity (total; 
moderate or severe) in each week of the first 4 weeks Double-blind Treatment Phase.
4. Mean change from baseline in the number of migraine days per month by pain intensity 
(total; moderate or severe) in each month and the entire course of the Open-label Extension 
Phase.
5. Proportion of subjects with 50% reduction, 75% reduction, and 100% reduction from 
baseline in the number of migraine days per month by pain intensity (total; moderate or 
severe) in each month and the entire course of the Open-label Extension Phase. 
6. Mean number of acute migraine-specific medication days per month and acute migraine 
medication days per month in each month and the entire course of the Double-blind 
Treatment Phase. Acute migraine medications are triptans, ergotamine, and other 
medications used to treat headache or aura.
7. Mean number of acute migraine-specific medication days per month and acute migraine 
medication days per month in each month and the entire course of the Open-label Extension 
Phase. 
8. Mean change from baseline in MSQoL domain scores (restrictive role function, preventive 
role function, emotional function), MIDAS scores (total, absenteeism, presenteeism), EQ-
5D-5L VAS score over time during the Double-blind Treatment Phase and Open-label 
Extension Phase.
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3.4. Definition of Migraine Days
A Migraine Day is defined as any calendar day which the subject experiences a qualified 
migraine headache (onset, continuation or recurrence of the migraine headache). A qualified 
migraine headache is defined as a migraine with or without aura, lasting for ≥30 minutes, and 
meeting at least one of the following criteria (A and/or B): 
A) ≥ 2 of the following pain features: 
▪
Unilateral location,
▪
Pulsating quality (throbbing),
▪
Moderate or Severe pain intensity, 
▪
Aggravation by or causing avoidance of routine physical activity (e.g., walking or 
climbing stairs)
B) ≥ 1 of the following associated symptoms: 
▪
Nausea and/or Vomiting, 
▪
Photophobia and phonophobia 
During the Double-blind Treatment Phase, if the subject takes an acute migraine-specific 
medication (i.e., triptan or ergotamine) during aura or to treat a headache on a calendar day, then 
it will be counted as a migraine day regardless of the duration and pain features/associated 
symptoms. The use of study medication on non-scheduled dosing days is only permitted during 
the Open-label Extension Phase. Dosing with study medication on non-scheduled dosing days 
is not permitted during the Double-blind Treatment Phase.
A moderate to severe migraine day is a migraine day with a migraine reported with moderate or 
severe pain intensity.
For the full definition of Migraine Days, please refer to Section 16.2 APPENDIX 2.
3.5. Definition of Headache Days
A Headache Day is any calendar day in which the subject experiences a qualified headache 
(initial onset, continuation, or recurrence of the headache). A qualified headache is defined as:

A qualified migraine headache (including an aura-only event that is treated with acute 
migraine-specific medication), or

A qualified non-migraine headache, which is a headache that lasts ≥ 30 minutes and is not a 
qualified migraine headache, or

A headache of any duration for which acute headache treatment is administered.
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4. STUDY PLAN
4.1. Study Design and Duration
This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy 
and safety of rimegepant in migraine prevention in Japanese subjects.
The study will randomize approximately 490 subjects in a 1:1 ratio to the rimegepant or placebo 
treatment groups. The randomization will be stratified by the use of prophylactic migraine 
medications (yes or no).
The Screening Phase includes a Screening Visit and a 28-day Observation Period. Upon 
completion of the Screening Visit, subjects will be provided an electronic diary (eDiary) to 
document migraine occurrence, migraine pain features and associated symptoms, and use of 
acute migraine medication on each day of the 28-day Observation Period. Subjects will record 
the standard of care migraine treatment taken on a paper diary. For subjects to be eligible for the 
study, they must report having had 4 to 18 migraine attacks of moderate to severe intensity per 4-
week period within the 12 weeks prior to the Screening Visit, and at least 4 migraine days and no 
more than 18 headache days during the 28-day Observation Period. After completing the 28-day 
observation period, the subject will return to the clinical with both diaries for the Baseline Visit.
At the Baseline Visit, eligibility for continued participation in the study will be assessed before 
randomization occurs and before study drug is dispensed. Subjects will be instructed that they 
must take 1 orally disintegrating tablet (ODT) of blinded study drug (rimegepant 75 mg or 
placebo) every other calendar day. If subjects have a migraine attack during the Double-blind 
Treatment Phase, if needed, they may treat the migraine attack with their standard of care 
medication and continue to take study drug on their regular schedule (scheduled dosing days 
only). 
At the completion of the 12-week Double-blind Treatment Phase, subjects may be entered into 
the 40-week Open-label Extension Phase following laboratory results within acceptable ranges. 
During the Open-label Extension Phase, subjects will be instructed that they must take 
1 rimegepant 75 mg every other calendar day. If subjects have a migraine on a day that they are 
not scheduled to dose with rimegepant, they may take 1 rimegepant 75 mg on that calendar day 
to treat a migraine. Therefore, during the Open-label Extension Phase, subjects can take a 
maximum of 1 rimegepant 75 mg ODT per calendar day up to 40 weeks.
Subjects are required to record their migraine occurrence, migraine pain features and associated 
symptoms, and use of acute migraine medication in the eDiary every day. Subjects are also 
required to record any rescue medication taken on a paper diary and WOCBP will record their 
menstrual period information on a paper log. 
At select study visits, subjects will complete or will be administered the Migraine-Specific 
Quality-of-Life Questionnaire v 2.1 (MSQoL v2.1), the Migraine Disability Assessment 
(MIDAS), EQ-5D-5L and the Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects will 
use the eDiary to assess MSQoL v2.1, MIDAS, and EQ-5D-5L.
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Study visits will occur at Screening (Enrollment), Baseline (Randomization), Week 2, Week 4, 
Week 8, and Week 12. At the completion of the 12-week Double-blind Treatment Phase, 
subjects may be entered into the 40-week Open-label Extension Phase following laboratory tests 
within normal ranges. Visits occur at Week 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52/ End of 
Treatment (EOT). Subjects will return to the study site at the end of Week 52 (+/-3 days) for the 
EOT Visit. Any subject who discontinues early, at any time during the study, will return to the 
study site for the EOT Visit. There is a Follow-up Visit 14 days (+/-2 days) after the EOT Visit.
Subjects who do not complete the Double-blind Treatment Phase and/or do not enter or complete 
the Open-label Extension Phase should complete the EOT and the Follow-up Week 2 Visits.
To closely monitor for potential drug induced liver injury, guidance on reporting potential drug-
induced liver injury (DILI) events is provided in the protocol. Laboratory results that meet 
predefined LFT abnormality criteria as potential DILI events should be reported as a serious 
adverse event (SAE).
4.2. Study Schematic
Figure 1
Study Schematic
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4.3. Schedule of Assessments
Table 1
Schedule of Assessments – Observation Period, Double-blind Treatment Phase
Observation Period 
(28 days + 3 days)9
Double-blind Treatment Phase9 10
Procedure
Screening 
Visit
Pre-randomization 
Evaluation Visit: within 
96 hours of Baseline 
(Randomization) Visit11
Baseline 
(Randomization) 
Visit (Day 0)
Week 2
(Day14 +/- 2 days)
Week 4
(Day 28 + 3 days)
Weeks 8 (Day 56) 
and 12 (Day 84)
(all visits + 3 days)
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
X
Medical History
X
Migraine History 
(signs/symptoms/prior 
treatment/frequency/intensity)
X
Rescue Medication paper 
diary, Concomitant 
Medication paper diary and 
Menstrual Period paper log 
(WOCBP)1
X
X
X
X
X
X
Enroll subject/IWRS
X
Randomize subject / IWRS2
X
Safety Assessments
Physical Examination
X
X
X
X
Vital Signs / Physical 
Measurements3
X
X
X
X
Clinical Safety Laboratory 
Testing
X
X
X
X
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Observation Period 
(28 days + 3 days)9
Double-blind Treatment Phase9 10
Procedure
Screening 
Visit
Pre-randomization 
Evaluation Visit: within 
96 hours of Baseline 
(Randomization) Visit11
Baseline 
(Randomization) 
Visit (Day 0)
Week 2
(Day14 +/- 2 days)
Week 4
(Day 28 + 3 days)
Weeks 8 (Day 56) 
and 12 (Day 84)
(all visits + 3 days)
Liver Function Test (LFTs)
X
X
X
X
X
X
Lipid Panel
X
X (week 12 only)
ECG
X
X
X
Urinalysis
X
Urine Drug Screen for drugs 
of abuse
X
FSH, if applicable, to 
determine WOCBP status
X
Pregnancy Test
X (urine)
X (serum)
X (urine)
X (urine)
X (urine)
AE, SAE, and Concomitant 
Procedure assessment4
X
X
X
X
X
X
Columbia-Suicide Severity 
Rating Scale (C-SSRS)
X
X
X
X
X
Clinical Drug Supplies / Study Supplies
Dispense Study drug5
X
X
X
Administer study drug6
X
X
X
Electronic Diary (eDiary) 
dispensed7
X
Enter use of study drug in 
paper diary
X
X
X
X
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Observation Period 
(28 days + 3 days)9
Double-blind Treatment Phase9 10
Procedure
Screening 
Visit
Pre-randomization 
Evaluation Visit: within 
96 hours of Baseline 
(Randomization) Visit11
Baseline 
(Randomization) 
Visit (Day 0)
Week 2
(Day14 +/- 2 days)
Week 4
(Day 28 + 3 days)
Weeks 8 (Day 56) 
and 12 (Day 84)
(all visits + 3 days)
Return unused study drug to 
site for compliance check
X
X
X
eDiary returned / reviewed for 
completeness
X
X
X
X
X
Efficacy Assessments
Daily report of migraine 
occurrence and pain intensity 
reported by subject in eDiary8
X
X
X
X
X
Other Assessments reported by subject in eDiary
MSQoL v2.18
X
X (week 12 only)
MIDAS8
X
X (week 12 only)
EQ-5D-5L8
X
X (week 12 only)
1 Concomitant medications, including prophylactic and standard of care migraine medications, taken during Observation Period and rescue medication taken 
during the Treatment Phase should be recorded in the subject’s paper diary and reviewed by study personnel at each visit. WOCBP will also record menstrual 
period information on the paper diary which should be reviewed by study personnel at each visit.
2 The actual baseline visit date should be used for IWRS enrollment date and eligibility date.
3 Height measured at Screening Visit only. Weight, body temperature, respiratory rate, blood pressure, and heart rate will be collected at all timepoints where 
indicated. Sitting arterial systolic and diastolic blood pressure and radial artery pulse rate will be measured.
4 SAEs, AEs, and Concomitant Procedures must be reported after subject signs informed consent. SAEs should be reported from signing of consent through the 
2-week Follow up Safety Visit. Non-serious AEs should be reported from signing of consent through 2-Week Follow up Safety Visit. 
5 Subjects should finish a wallet of study drug before starting a new wallet. Study drug will be dispensed at monthly (every 4 weeks) study visits, as needed. 
Unscheduled visits to dispense study drug may be scheduled as needed. In cases the COVID-19 Pandemic impacts study visits, study medication may be 
delivered to a subject per local regulation, with up to a 4-week supply. When delivered by courier, site must select a courier that provides trackable delivery 
service and proper documentation must be maintained in the subject’s source records including shipping vendor, tracking number, confirmation of receipt by 
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subject/family, and all other relevant information. Study medication at Baseline and Week 12 must not be shipped by the sites to subjects. At the Week 12 
Visit, the open-label study drug will be dispensed and subjects will be instructed not to begin taking rimegepant until confirmation from site staff pending lab 
results.
6 Subjects must take their study drug every other day, regardless of whether or not they have a migraine. Subjects must report each ODT they take in the paper 
diary. Doses are not required to be taken in the office on days of a study visit, however dosing requirements and compliance should be discussed with subjects 
at all visits. 
7 The electronic subject diary (eDiary) will be dispensed at the Screening Visit, after all Screening Procedures are completed. The subject will be trained on the 
use of the eDiary. 
8 Subjects will use the eDiary every day during the Observation Period and Double-blind Treatment Phase to report migraine occurrence, migraine pain features 
and associated symptoms, and use of acute migraine medication. Subjects will use the eDiary at select visits to assess MSQoL v2.1, MIDAS, and EQ-5D-5L. 
9 While on-study, all visit windows are used for scheduling purposes and all efforts should be made to return subjects to the 14 or 28-day schedule if scheduling 
changes are made at any previous visit(s). In cases the COVID-19 Pandemic impacts study visits, visits between Week 2 and Week 8, inclusive, may be 
conducted remotely (e.g., telephone, telemedicine) with at least, but not limited to the following procedures completed: assessment of contraception, AE, SAE, 
and concomitant procedure assessment, and compliance check of study drug. The visits must be documented within the source records as being conducted 
remotely. At Week 4 and Week 8, these procedures conducted remotely must be completed before dispensing study drug. All procedures not able to be 
completed due to a visit being conducted remotely must be reported as a protocol deviation. In such cases, investigators should schedule a visit to perform all 
on-site procedures which cannot be completed remotely at their earliest convenience.
10 Subjects who do not complete the Double-blind Treatment Phase or do not enter the Open-label Extension Phase should complete the End of Treatment Visit 
and 2-Week Follow-up Safety Visit.
11 The duration between the Pre-randomization Evaluation Visit and the Baseline (Randomization) Visit is 4 days. The “+2” days window is included for 
scheduling purposes only. Every effort should be made to collect the Pre-randomization Evaluation Visit samples as close to, and within, the 4 days prior to 
the Baseline Visit as possible. However, for scheduling convenience, this window may be up to 6 days (between the Pre-randomization Evaluation Visit and 
the Baseline Visit).
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Table 2
Schedule of Assessments – Open-label Treatment Phase, Follow-up Visits
Procedure
Phone
visit
Week 14 
(Day 98)10
(± 3 days)
Week 16
(Day 112) 10
(± 3 days)
Week 20 (Day 140) to Week 52 
(Day 364) / EOT
Visits every 4 weeks10
(± 3 days)
2-Week Follow-up 
Safety Visit10
(14 days after EOT visit 
± 2 days)
Confirm eligibility based on Week 12 
Laboratory Results1
X
Rescue Medication paper diary, 
Concomitant Medication paper diary and 
Menstrual Period paper log (WOCBP)2
X
X
X
X3
Safety Assessments
Physical Examinations
X
X (Week 24 and 52 / EOT only)
Vital Signs / Physical Measurements4
X
X
X
Clinical Safety Laboratory Testing
X
X (Week 24 and 52 / EOT only)
Liver function tests (LFTs)
X
X
X
X
Lipid Panel
X (Week 24 and 52 / EOT only)
ECG
X
X (Week 24 and 52 / EOT only)
X
Urinalysis
X (Week 52 / EOT only)
Pregnancy Test
X (urine)
X (urine)
X (serum)
AE, SAE, and Concomitant Procedure 
Assessment5
X
X
X
X
Columbia-Suicide Severity Rating Scale 
(C-SSRS)
X
X
X
X
Clinical Drug Supplies / Study Supplies
Dispense Study drug 1, 6
X
X
all visits except Week 52 / EOT
Administer Study drug7
X
X
X
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Procedure
Phone
visit
Week 14 
(Day 98)10
(± 3 days)
Week 16
(Day 112) 10
(± 3 days)
Week 20 (Day 140) to Week 52 
(Day 364) / EOT
Visits every 4 weeks10
(± 3 days)
2-Week Follow-up 
Safety Visit10
(14 days after EOT visit 
± 2 days)
Enter Use of Study drug in paper diary
X
X
X
Return unused study drug to site for 
compliance check
X
X
X
eDiary returned/reviewed for completeness8
X
X
X
Efficacy Assessments
Daily report of migraine occurrence and pain 
intensity reported by subject in eDiary9
X
X
X
Other Assessments reported by subject in eDiary
MSQoL v2.19
X (Weeks 24 and 52 / EOT only)
MIDAS9
X (Weeks 24 and 52 / EOT only)
EQ-5D-5L9
X (Weeks 24 and 52 / EOT only)
1 Study eligibility must be confirmed by Week 12 laboratory results prior to first dose of study medication, which is dispensed at the Week 12 Visit. Sites must 
contact subject by phone to confirm study eligibility prior to subject taking first dose.
2 Concomitant medications, including prophylactic and rescue medications, taken during the Open-label Extension Phase should be recorded in the subject’s 
paper diary and reviewed by study personnel at each visit. WOCBP will also record menstrual period information on the paper log which should be reviewed 
by study personnel at each visit.
3 Collect if treatment with concomitant medication is required for an AE or if concomitant medication is considered related to AE.
4 Weight, body temperature, respiratory rate, blood pressure, and heart rate will be collected at all timepoints where indicated. Sitting arterial systolic and 
diastolic blood pressure and radial artery pulse rate will be measured.
5 SAEs, AEs, and Concomitant Procedures must be reported after subject signs informed consent. SAEs should be reported from signing of consent through the 
2-week Follow up Safety Visit. Non-serious AEs should be reported from signing of consent through 2-Week Follow up Safety Visit.
6 Subjects should finish a wallet of study drug before starting a new wallet. Study drug will be dispensed at monthly (every 4 weeks) study visits, as needed. 
Unscheduled visits to dispense study drug may be scheduled as needed. In cases the COVID-19 Pandemic impacts study visits, study medication may be 
shipped to a subject per local regulation, with up to a 4-week supply. When delivered by courier, site must select a courier that provides trackable delivery 
service and proper documentation must be maintained in the subject’s source records including shipping vendor, tracking number, confirmation of receipt by 
subject/family, and all other relevant information.
7 Subjects must take their study drug every other day, regardless of whether or not they have a migraine. During the Open-label Extension Phase only, if subjects 
have a migraine on a day that they are not scheduled to take a study drug, if needed, they may take a study drug to treat a migraine on that calendar day. 
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Therefore, subjects can take a maximum of 1 ODT of study drug per calendar day. Subjects must report each ODT they take in the paper diary. Doses are not 
required to be taken in the office on days of a study visit, however dosing requirements and compliance should be discussed with subjects at all visits. 
8 During the Open-label Extension Phase, subjects with 6 or more missed reports and 3 or more missed dosing entries per month for 2 months (sequential or 
non-sequential months) should be considered for discontinuation from the study for poor compliance, after discussion with Sponsor. Month is defined as 4 
weeks for the purpose of this protocol.
9 Subjects will be trained on the use of the eDiary. The subject will use the eDiary every day during the Open-label Extension Phase to report migraine 
occurrence, migraine pain features and associated symptoms, and use of acute migraine medication. Subjects will use the eDiary at select visits to assess 
MSQoL v2.1, MIDAS, and EQ-5D-5L.
10 While on-study, all visit windows are used for scheduling purposes and all efforts should be made to return subjects to the 14 or 28-day schedule if scheduling 
changes are made at any previous visit(s). In cases the COVID-19 Pandemic impacts study visits, visits may be conducted remotely (e.g., telephone, 
telemedicine) with at least, but not limited to the following procedures completed: assessment of contraception, AE, SAE, and concomitant procedure 
assessment, and compliance check of study drug. The visits must be documented within the source records as being conducted remotely. These procedures 
conducted remotely must be completed before dispensing study drug. All procedures not able to be completed due to a visit being conducted remotely must be 
reported as a protocol deviation. In such cases, investigators should schedule a visit to perform all on-site procedures which cannot be completed remotely at 
their earliest convenience.
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4.3.1. Observation Period
The Observation Period will be 28 days + 3 days. Note that the “+ 3 days” window is included 
for scheduling purposes only. The Observation Period will have 2 scheduled visits, Screening 
and Pre-randomization Evaluation, which should be completed in person.
4.3.1.1. Screening Visit
Before any study procedures are performed, subjects must provide documented informed 
consent. After informed consent, subjects will be enrolled in the IWRS system. The subject’s 
migraine history and medical history will be collected at the Screening Visit, which starts at 
day 1 of the Observation Period. Subjects will undergo all screening procedures as detailed in
Table 1. After completion of all screening procedures, subjects will be provided an eDiary. 
Subjects will report migraine occurrence, migraine pain features and associated symptoms, and 
use of acute migraine medication in the eDiary every day during the Observation Period. All 
subjects will continue to use their acute standard of care migraine medications during the 
Observation Period. Subjects will record all concomitant medications, including acute standard 
of care migraine medications (both prescribed and OTC), taken during the entire Observation 
Period in a concomitant medication paper diary. WOCBP will record their menstrual period 
information on a paper log.
If the subject meets study entry criteria (i.e., inclusion/exclusion criteria), the subject will return 
to the study site for the Pre-randomization Evaluation Visit. If the subject does not meet study 
entry criteria, the subject will be considered a screen failure and should be recorded as such in 
IWRS. The subject must return to the study site to return the eDiary. If a LFT abnormality is 
observed at the screening visit, the repeat sample can be obtained as part of an unscheduled 
assessment for confirmation, and, if within the protocol defined eligibility criterion, it would be 
obtained at the scheduled time at the Pre-randomization Evaluation Visit. If the result of that test 
meets the protocol defined eligibility criterion, the subject can be enrolled if otherwise eligible.
Subjects who resulted in screening failures at the Pre-randomization Evaluation Visit or earlier 
under one of the previous protocols and who are reasonably expected to be eligible provided the 
ineligibility was due to one of the eligibility items modified in the protocol amendment may be 
considered for re-screening. Subjects who were screen failures due to select circumstances and 
who are reasonably expected to be eligible (e.g., previously pregnant, screening window too 
long) may also be considered for re-screening. In all possible re-screening circumstances, the 
situation may be discussed with the Sponsor prior to re-screening and a new subject number 
must be obtained from the appropriate study-related system. Re-screening will only be permitted 
one time. 
4.3.1.2. Pre-randomization Evaluation Visit
Within 96 hours +48 hours (4 days +2 days) of the Baseline (Randomization) Visit, subjects 
must return to the study site for the Pre-randomization Evaluation Visit. This visit occurs within 
the Observation Period. Safety labs and a serum pregnancy test for WOCBP will be obtained and 
compliance with the eDiary will be assessed. If the subject continues to meet study entry criteria 
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and laboratory test results are acceptable per protocol, the subject will be randomized at the 
Baseline Visit into the Double-blind Treatment Phase. If the laboratory results are not acceptable 
per protocol, the subject is determined to be a Screen Failure and must return to the study site to 
return the eDiary. Repeat testing because of LFT abnormalities will not be permitted. Subjects 
who do not meet eligibility criteria at the Pre-randomization Evaluation Visit may NOT be 
re-tested between this visit and the baseline (randomization) visit and must be screen failed. 
However, they may be able to be re-screened under a new subject number in select circumstances 
and after agreement by the Sponsor as described in Section 4.3.1.1.
4.3.2. Randomized, Double-Blind Treatment Phase (12 weeks)
The Double-blind Treatment Phase will be up to 12 weeks from the Baseline (Randomization) 
Visit through the Week 12 or EOT Visit. 
During the Double-blind Treatment Phase, subjects will be instructed that they must take 1 ODT 
of blinded study drug every other calendar day, regardless of whether they have a migraine on 
that day or not. If subjects have a migraine during the Double-blind Treatment Phase, if needed, 
they may treat the migraine with their standard of care medication and continue to take study 
drug on their regular schedule (scheduled dosing days only).
NOTE: During the Double-blind Treatment Phase, if a dose of study drug for a given day is 
missed, lost, or otherwise unable to be taken, the subject should document that as a missed dose 
on the study drug wallet and should NOT take another dose of study medication until the next 
scheduled dosing day in accordance with the planned EOD dosing schedule.  
Subjects will continue to report migraine occurrence, migraine pain features and associated 
symptoms and use of acute migraine medication in the eDiary every day during the Double-blind 
Treatment Phase.
The MSQoL v2.1, MIDAS, EQ-5D-5L and C-SSRS will be completed, or administered by the 
investigator, at specified study visits (Table 1). Subjects will use the eDiary to assess MSQoL 
v2.1, MIDAS, and EQ-5D-5L.
Subjects will continue to record all concomitant medications, including acute standard of care 
migraine medications (both prescribed and OTC), taken during the entire Double-blind 
Treatment Phase in a concomitant medication paper diary.
After the Baseline Visit, study visits will be approximately every 2 weeks during the first month, 
and then every 4 weeks until the Week 12 or EOT Visit (Table 1). At each visit, the eDiary will 
be reviewed by site staff for completeness and compliance. Menstrual period information 
(WOCBP) will be also reviewed. 
Study drug compliance will be reviewed at each visit using the returned study drug wallets. 
Unused, non-expired, partial wallets will be returned to the subjects for completion prior to 
starting a new wallet. Subjects will be dispensed additional study drug as needed, as per the IP 
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manual. Additional safety tests (including laboratory tests and ECGs) will be performed per the 
schedule outlined in Table 1. 
Subjects in the Double-blind Treatment Phase who demonstrate poor compliance will be 
discussed with the Sponsor, corrective training will be completed by the site with the subject and 
may not be considered for the Open-label Treatment Phase. 
4.3.2.1. Baseline (Randomization) Visit
Once completing the Observation Period, subjects will return to the study site for the Baseline 
(Randomization) Visit, which should be completed in person. Subjects who continue to meet all 
study entry criteria and have had good compliance with the eDiary completion may enter the 
Double-blind Treatment Phase, pending review of additional laboratory test results. 
Because laboratory results from the Baseline (Randomization) Visit will be available after the 
subject may have been determined to be otherwise eligible for the study, had been randomized, 
and started treatment, there is the possibility that exclusionary laboratory results from the 
Baseline Visit may result in early discontinuation from the study.
Subjects with fewer than 24 completed eDiary reports in the Observation Period will not be 
considered for participation due to non-compliance with the eDiary. 
4.3.2.2. Week 12 or EOT Visit
Subjects will return to the study site at the Week 12 Visit (Day 85 +3 days), or at the EOT Visit 
for early discontinuation, for review of the eDiary, assessment of medication compliance and 
assessment of tolerability and safety (including vital signs, laboratory tests, and 
electrocardiography) (Table 1).  
Subjects must return the unused study drug and eDiary to the study site. Subjects in the Double-
blind Treatment Phase who demonstrate poor compliance will be discussed with the Sponsor, 
corrective training will be completed by the site with the subject and may not be considered for 
the Open-label Extension Phase. 
All randomized subjects who discontinue early from the Double-blind Treatment Phase should 
complete the EOT Visit. Otherwise, subjects should complete the Week 12 Visit. 
In cases where the subject does not enter the Open-label Extension Phase, the subject should 
return to the site for the Follow-up Week 2 Visit (2 weeks ± 2 days after the Week 12 or EOT 
Visit), to complete all procedures. 
4.3.3. Open-label Extension Phase (40 weeks)
It is estimated that approximately 400 subjects will be entered into the Open-label Extension 
Phase.
As indicated in Table 1, laboratory tests will be performed at the Week 12 Visit (final visit of the 
Double-blind Treatment Phase). Subjects who (1) complete the Double-blind Treatment Phase, 
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(2) continue to meet all inclusion/exclusion criteria, and (3) have been compliant with the eDiary 
may enter the Open-label Extension Phase, pending review of laboratory test results. 
Subjects will be dispensed study drug (rimegepant 75 mg) and must be instructed that they 
cannot take study drug until laboratory results confirm study eligibility. Subjects may be 
contacted by telephone; an office study visit is not required. 
Subjects will be instructed that they must take 1 ODT of rimegepant 75 mg every other calendar 
day, regardless of whether they have a migraine on that day. If subjects in this group have a 
migraine on a day that they are not scheduled to dose with study drug, they may take 1 study 
drug ODT on that calendar day to treat a migraine. Therefore, if needed, subjects can take a 
maximum of 1 ODT of study drug per calendar day for 40 weeks during the Open-label 
Treatment Phase.
NOTE: During the Open-label Extension Phase, if a dose of study drug for a given day is 
missed, lost, or otherwise unable to be taken, the subject should document that as a missed dose 
on the study drug wallet and should NOT take the scheduled dose of study medication until the 
next scheduled dosing day in accordance with the planned EOD dosing schedule.  
Subjects will continue to report migraine occurrence, migraine pain features and associated 
symptoms and use of acute migraine medication in the eDiary every day during the Open-label 
Extension Phase.
The MSQoL v2.1, MIDAS, EQ-5D-5L and C-SSRS will be completed, or administered by the 
investigator, at specified study visits (Table 2). Subjects will use the eDiary to assess MSQoL 
v2.1, MIDAS, and EQ-5D-5L.
Subjects will continue to record all concomitant medications, including acute standard of care 
migraine medications (both prescribed and OTC), taken during the entire Open-label Treatment 
Phase in a concomitant medication paper diary.
Study visits will be approximately every 2 weeks during the first month and then every 4 weeks, 
until Week 52 (Table 2). At each visit, the eDiary will be reviewed by site staff for completeness 
and compliance. Concomitant medication use will be reviewed and compared between the 
eDiary and concomitant medication paper diary entries, where applicable at each visit. Menstrual 
period information (WOCBP) will be also reviewed. 
Study drug compliance will be reviewed at each visit using the returned study drug wallets, and 
subjects will be dispensed additional study drug as needed. Additional safety tests (including 
laboratory tests and ECGs) will be performed per the schedule outlined in Table 2.
4.3.3.1. Week 52 or EOT Visit
Subjects will return to the study at the end of Week 52 (± 3 days), or at end of treatment for early 
discontinuations, for review of the electronic diary, assessment of medication compliance, 
assessment of tolerability and safety (including vital signs, laboratory tests, and 
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electrocardiography) (Table 2). Subjects must return the unused study drug and electronic 
subject diary to the study site. 
All randomized subjects who discontinue early from the Open-label Extension Phase should 
complete the EOT Visit. Otherwise, subjects should complete the Week 52 Visit.
4.3.4. Follow-up Period
The Follow-up Period will have one scheduled visit, Follow-up Week 2. The visit should occur 
approximately 2 weeks after the last visit in the last treatment phase (i.e., Week 12/EOT Visit if 
the subject did not enter the Open-label Extension Phase; Week 52/EOT Visit if the subject 
entered the Open-label Extension Phase). 
All randomized subjects should complete the Follow-up Week 2 Visit, regardless of completing 
either treatment phase. Subjects will continue to record all concomitant medications, including 
acute standard of care migraine medications (both prescribed and OTC), taken during the entire 
Follow-up Period in a concomitant medication paper diary.
4.3.4.1. Follow-up Week 2 Visit
Subjects will return to the study site approximately 2 weeks (14 days +/- 2 days) after the last 
visit in the last treatment phase to collect vital signs, ECG, LFTs, assessment of AEs/SAEs, to 
have the C- SSRS performed, and to have a serum pregnancy test performed (WOCBP). 
Subjects will return the prophylactic and rescue medication paper diary and menstrual period 
(WOCBP) paper logs which should be reviewed one final time by study staff. Subjects must 
continue to track any concomitant medications and therefore must maintain the concomitant 
medication paper diary through this visit. 
Investigators should assess subjects for AEs consistent with drug dependency or withdrawal 
effects and report as appropriate (Section 7.4).
4.4. Post Study Access to Therapy (if applicable)
At the end of the study the sponsor will not continue to supply study drug to subjects or 
investigators. The investigator should ensure that the subject receives appropriate standard of 
care to treat the condition under study.
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5. POPULATION
Individuals entered in this trial will be subjects who suffer from migraines. The treatment setting 
for subjects may include headache clinics, hospitals or private practices, Subjects may be 
recruited from a variety of sources including referrals or professional recruitment agencies.
5.1. Number of Subjects
Approximately 1064 subjects will be screened to randomize up to approximately 490 subjects 
(245 subjects to each of the rimegepant or placebo groups). It is estimated that approximately 
400 subjects will be entered into the Open-label Extension Phase.
5.2. Inclusion Criteria
1. Signed Written Informed Consent
a. Written informed consent must be obtained from the subject in accordance with 
requirements of the study center’s institutional review board (IRB) or ethics committee, 
prior to the initiation of any protocol-required procedures.
2. Target Population; Subject has at least 1 year history of migraine (with or without aura) 
consistent with a diagnosis according to the International Classification of Headache 
Disorders, 3rd Edition13, including the following:
a. Age of onset of migraines prior to 50 years of age.
b. Migraine attacks, on average, lasting 4 to 72 hours if untreated
c. Per subject report, 4 to 18 migraine attacks of moderate or severe intensity per month 
within the last 3 months prior to the Screening Visit (month is defined as 4 weeks for the 
purpose of this protocol).
d. 4 or more migraine days during Observation Period. 
e. Not more than 18 headache days during the Observation Period.
f.
Ability to distinguish migraine attacks from tension/cluster headaches.
g. Subjects on prophylactic migraine medication are permitted to remain on therapy if the 
dose has been stable for at least 3 months (12 weeks) prior to the Observation Period, and 
the dose is not expected to change during the course of the study.
i.
Subjects may remain on one (1) medication with possible migraine-prophylactic 
effects regardless of indication, excluding CGRP antagonists [biologic or small-
molecule], during the Double-Blind Treatment Phase. See section 5.5. 
ii.
Concomitant use of a CGRP antagonist, such as erenumab or fremanezumab, is 
prohibited.
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iii.
Subjects who previously discontinued prophylactic migraine medication must 
have done so at least 90 days prior to the Screening Visit.
h. Subjects with contraindications for use of triptans may be included provided they meet all 
other study entry criteria.
3. Age and Reproductive Status
a. Male and female subjects ≥ 18 years. 
b. Women of childbearing potential (WOCBP) and non-sterile men must be using two 
acceptable methods of contraception to avoid pregnancy throughout the study in such a 
manner that the risk of pregnancy is minimized. Males with vasectomy are considered 
surgically sterile provided the procedure occurred greater than 6 months (24 weeks) prior 
to study participation.
c. At the Baseline Visit, WOCBP must have a negative pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) before dosing with study drug.
d. Women must not be pregnant, lactating or breastfeeding.
4. Other Inclusion Criteria
a. No clinically significant abnormality identified on the medical or laboratory evaluation. 
A subject with a clinical abnormality or laboratory parameters outside the reference range 
may be included only if the investigator considers the finding not clinically significant, 
that it will not introduce additional risk factors, nor interfere with the study procedures.
5.3. Exclusion Criteria
1. Target Disease Exclusion
a.
Subject has a history of migraine with brainstem aura (basilar migraine), hemiplegic 
migraine or retinal migraine.
b. Subjects with headaches occurring 19 or more days per month (migraine or non-
migraine) in any of the 3 months prior to the Screening Visit.
c.
History of systemic use of analgesics (e.g., nonsteroidal anti-inflammatory drugs 
[NSAIDs] or acetaminophen) on ≥ 15 days per month during the 3 months (12 weeks) 
prior to the Screening Visit.
2. Medical History and Concurrent Diseases
a.
Subject with a history of human immunodeficiency virus (HIV) disease.
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b. Subject history with current evidence of uncontrolled, unstable or recently diagnosed 
cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and 
cerebral ischemia. Subjects with myocardial infarction (MI), acute coronary syndrome 
(ACS), percutaneous coronary intervention (PCI), cardiac surgery, stroke or transient 
ischemic attack (TIA) during the 6 months (24 weeks) prior to screening. 
c.
Uncontrolled hypertension or uncontrolled diabetes (however, subjects can be included 
who have stable hypertension and/or diabetes for 3 months (12 weeks) prior to 
screening). Blood pressure greater than 150 mm Hg systolic or 100 mm Hg diastolic after 
10 minutes of rest is exclusionary.
d. Subjects with major depressive episode within the last 12 months, major depressive 
disorder or any anxiety disorder requiring more than 1 medication for each disorder. 
Medications to treat major depressive disorder or an anxiety disorder must have been at a 
stable dose for at least 3 months prior to the Screening Visit.
e.
Active chronic pain syndromes (such as fibromyalgia, chronic pelvic pain, complex 
regional pain syndrome [CRPS]).
f.
Subjects with other pain syndromes (including trigeminal neuralgia), psychiatric 
conditions, dementia, or significant neurological disorders (other than migraine) that, in 
the Investigator’s opinion, might interfere with study assessments.
g. Subject has current diagnosis of major depressive disorder requiring treatment with 
atypical antipsychotics, schizophrenia, bipolar disorder, or borderline personality 
disorder.
h. Subject has a history of gastric, or small intestinal surgery (including Gastric Bypass, 
Gastric Banding, Gastric Sleeve, Gastric Balloon, etc.), or has a disease that causes 
malabsorption. 
i.
Subject has any active hepatic or biliary disorder.
j.
The subject has a history or current evidence of any unstable medical conditions (e.g., 
history of congenital heart disease or arrhythmia, known or suspected infection, hepatitis 
B or C, or cancer) that, in the investigator’s opinion, would expose them to undue risk of 
a significant adverse event (AE) or interfere with assessments of safety or efficacy during 
the course of the trial.
k. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 months 
(48 weeks) or subjects who have met DSM-V criteria for any significant substance use 
disorder within the past 12 months (48 weeks) from the date of the Screening Visit.
l.
History of use of opioid- or barbiturate- (e.g., butalbital) containing medication for 4 or 
more days per month during the 3 months (12 weeks) prior to Screening Visit. 
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m. Subjects should be excluded if they have a positive drug screen for drugs of abuse that in 
the investigator’s judgment is medically significant, in that it would impact the safety of 
the subject or the interpretation of the study results. In addition:
i.
Detectable levels of cocaine, amphetamine, phencyclidine (PCP) and 
tetrahydrocannabinol (THC) in the drug screen are exclusionary. Subjects who 
have positive drug screen for amphetamines and who are on a prescribed 
amphetamine medication for an approved indication (e.g., ADHD) will be 
allowed into the study at the Investigator’s discretion. The determination by the 
Investigator must be well documented in the subject’s source medical records. 
The stimulant dose must be stable from 3 months (12 weeks) prior to baseline 
until the End of Treatment Visit occurs.
n. Hematologic or solid malignancy diagnosis within 5 years prior to screening. Subjects 
with a history of localized basal cell or squamous cell skin cancer are eligible for the 
study if they are cancer-free prior to the Screening Visit in this study.
o. Body mass index > 35.0 kg/m2.
p. History of gallstones or cholecystitis within past year. 
3. Allergies and Adverse Drug Reactions
a.
History of drug or other allergy which, in the opinion of the investigator, makes the 
subject unsuitable for participation in the study.
4. Sex and Reproductive Status
a.
WOCBP who are unwilling or unable to use an acceptable contraceptive method or 
abstinence to avoid pregnancy for the entire study period and for up to 60 days after last 
dose of study drug.
b. Women with a positive pregnancy test at screening or prior to study drug administration.
5. ECG and Laboratory Test Findings
a.
Estimated glomerular filtration rate (eGFR) ≤ 40 ml/min/1.73m2.
b. Corrected QT interval > 470 msec (QTc by method of Fridericia), at Screening.
c.
Left Bundle Branch block.
d. Right Bundle Branch Block with a QRS duration ≥ 150 msec.
e.
Intraventricular Conduction Defect with a QRS duration ≥ 150 msec.
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f.
T bili > 1.5 × ULN (may be repeated once for confirmation at Screening; refer to Sections 
4.3.1.1 and 4.3.1.2; direct bilirubin >1.5 × ULN is exclusionary for Gilbert’s syndrome).
g. AST or ALT > 1.5 × ULN (may be repeated once for confirmation at Screening; refer to 
Sections 4.3.1.1 and 4.3.1.2).
h. Neutrophil count ≤ 1000/μL (or equivalent).
i.
HbA1c > 7.5%.
6. Prohibited Medications
a.
Subjects taking a prohibited medication (refer to Section 5.4).
7. Other Exclusion Criteria
a.
Subjects are excluded if they have had no therapeutic response with > 2 of the medication 
categories for prophylactic treatment of migraine (see Section 16.3 APPENDIX 3) after 
an adequate therapeutic trial.
b. Non-compliance with or inability to complete eDiary during Observation Period. 
Subjects with less than 24 completed eDiary reports during the Observation Period will 
not be considered for participation due to non-compliance with the eDiary. 
c.
Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness.
d. Exposure to non-biological investigational agents or investigational interventional within 
the 30 days prior to Screening Visit.
e.
Exposure to biological investigational agents within the 90 days prior to Screening Visit. 
f.
Subjects who have previously participated in any study of rimegepant.
g. Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 12 
months prior to the Screening Visit, OR subjects who endorse any of the 5 C-SSRS 
Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory 
acts, or behavior) within the last 10 years prior to the Screening Visit, OR subjects who, 
in the opinion of the investigator, present a serious risk of suicide (See Section 6.2.5).
h. Participation in any other investigational clinical trial while participating in this clinical 
trial.
i.
Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
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5.4. Prohibited and Restricted Concomitant Medications
The medications listed below are prohibited starting at the Baseline Visit and during the course 
of this study or as specified. 
1. Traditional Chinese Medicines should not be taken 14 days prior to Screening Visit and 
throughout the study.
2. St. John’s Wort should not be taken 14 days prior to the Baseline visit and throughout the 
study.
3. Barbiturate-containing products (e.g., Fioricet, Fiorinal, butalbital, phenobarbital) should not 
be taken 14 days prior to randomization and throughout the study.
4. Modafinil (PROVIGIL®) should not be taken 14 days prior to randomization and throughout 
the study.
5. Butterbur root or extracts should not be taken 14 days prior to the Baseline Visit and 
throughout the study.
6. History of use of ergotamine medications on > 10 days per month on a regular basis for > 3
months (> 12 weeks).
7. Use of narcotic medication, such as opioids (e.g., morphine, codeine, oxycodone and
hydrocodone) or barbiturates is prohibited starting from 2 days prior to the Baseline Visit and 
throughout the study. 
8. Systemic use of analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] or 
acetaminophen) on ≥ 15 days per month is prohibited during the study.
9. Use of acetaminophen or acetaminophen containing products for non-headache indications 
after the Baseline Visit is prohibited. Any use of acetaminophen or acetaminophen 
containing products for non-headache indications during the Observation Period must be
stopped at least 2 days prior to Baseline Visit. 
10. Use of triptans is prohibited during the Open-label Extension Phase. 
11. Lasmiditan (Reyvow®) is prohibited 14 days prior to randomization and throughout the 
study.
12. The use of CGRP antagonists (biologic [e.g., Aimovig™ and Ajovy™ or Emgality®] or 
small molecule) other than rimegepant provided as study drug is prohibited during the study. 
CGRP antagonist biologics must be discontinued 6 months prior to screening and are 
prohibited throughout the study.
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13. The use of oral gepants must be discontinued 2 weeks prior to screening and are prohibited 
throughout the study (e.g., ubrogepant, atogepant). Any past exposure to rimegepant will be 
exclusionary.
14. Use of marijuana and all forms of ingested or inhaled cannabidiol (CBD) and THC-
containing products are prohibited during the study. 
15. Concomitant use of moderate to strong CYP3A4 inhibitors with rimegepant is prohibited 
during the study. If use of a moderate to strong CYP3A4 inhibitor is required during the 
Open-label Extension Phase, such as use of HIV Protease Inhibitors, Hepatitis C protease 
inhibitors, certain azole antifungals, or clarithromycin, dosing with rimegepant should be 
stopped and should not start again until 14 days after the last dose of the moderate to strong 
CYP3A4 inhibitor. See Section 16.1 APPENDIX 1.
16. Concomitant use of moderate to strong CYP3A4 inducers with rimegepant is prohibited 
during the study. If use of a moderate to strong CYP3A4 inducer is required during the 
Open-label Extension Phase, dosing with rimegepant should be stopped and should not start 
again until 14 days after the last dose of the moderate to strong CYP3A4 inducer. See 
Section 16.1 APPENDIX 1.
17. Concomitant use of strong inhibitors of the P-glycoprotein (P-gp) transporter with 
rimegepant is prohibited during the study. See Section 16.1 APPENDIX 1.
18. Concomitant use of atypical antipsychotics such as Abilify® (aripiprazole), Zyprexa®
(olanzapine), Seroquel® (quetiapine), Geodon® (ziprasidone), or Risperdal® (risperidone) is 
prohibited during the study.
19. Concomitant use of LAMICTAL® (lamotrigine) is prohibited during the study.
20. Use of CefalyTM or any other device for migraine treatment is prohibited within 12 weeks of 
the Screening Visit and during the study. 
21. Use of any investigational agent other than rimegepant from the Screening Visit through the 
2-Week Follow-up Safety Visit.
22. Low dose aspirin (up to 100 mg daily) for documented cardiovascular prophylaxis is 
allowed.
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5.5. Prophylactic and Rescue Medications
Subjects may not use more than 1 of the following medications with possible migraine-
prophylactic effects if not otherwise prohibited by the protocol. Doses must be stable within 3 
months (12 weeks) prior to the start of the Observation Period and throughout the study. Use 
of more than 1 of the following medications is prohibited within 3 months (12 weeks) prior to 
the start of the Observation Period and throughout the study.
Prophylactic migraine medications that are permitted during the study include:

Topiramate, gabapentin

Valproic acid/valproate (permitted if subject is on therapy for at least 6 months prior to the 
Screening Visit)

Beta blockers (such as: atenolol, bisoprolol, metoprolol, nadolol, nebivolol, pindolol, 
propranolol, timolol)

Tricyclic antidepressants (such as: amitriptyline, nortriptyline, protriptyline)

Venlafaxine, desvenlafaxine, duloxetine, milnacipran

Flunarizine, lomerizine

Lisinopril, candesartan

Clonidine, guanfacine

Cyproheptadine

Methysergide

Pizotifen

Feverfew, magnesium (≥ 600 mg/day), riboflavin (≥ 100 mg/day)

Botulinum toxin injections (e.g., Botox®)

The use of CGRP antagonists (biologic [e.g., Aimovig™, Ajovy™ or Emgality®] or small 
molecule) other than rimegepant as study drug is prohibited during the study.
The use of triptan medications is prohibited during the Open-label Extension Phase of the study, 
but is allowed as rescue medication during the Double-blind Treatment Phase.
Subjects may use their permitted standard of care medication if needed for acute treatment of a 
migraine and record any medications taken on the appropriate paper diary. Permitted 
medications include the following rescue medications: 
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
triptans (triptans are prohibited during the Open-label Extension Phase after Week 12)

aspirin

ibuprofen

baclofen

acetaminophen up to 2000 mg/day for a maximum of 2 consecutive days at a time (this 
includes Excedrin Migraine)

naprosyn (or any other type of non-steroidal anti-inflammatory drug (NSAID))

antiemetics (e.g., metoclopramide or promethazine)

muscle relaxants for rescue during the study
These are the only medications allowed for rescue. Subjects should continue taking study drug 
on scheduled dosing days.
If a subject takes study drug and experiences a migraine later that day, after taking study drug for 
the day, the subject may take their rescue medication as described in this section of the protocol. 
During the Double-blind Treatment Phase, subjects are not allowed to take more than 1 ODT 
of study drug EVERY OTHER calendar day. During the Open-label Extension Phase, 
subjects are required to take 1 ODT of study drug every other day, but may also take 1 ODT of 
study drug on non-scheduled dosing days to treat a migraine. Subjects are not allowed to take 
more than 1 ODT of study drug per calendar day during the Open-label Extension Phase.
Use of standard of care medication during Observation Period and use of rescue medication 
during the Double-blind Treatment Phase, Open-label Extension Phase, and standard of care 
medication through to the 2-Week Follow-up Safety Visit will be recorded by the subject on a 
paper diary and reported to the site. 
5.6. Women of Childbearing Potential
Women of childbearing potential (WOCBP) includes any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or is not postmenopausal. Menopause is defined as:
1. Amenorrhea greater than or equal to 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL at screening or
2. Woman with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL at screening or
3. Woman on hormone replacement therapy (HRT) who no longer menstruate
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NOTE: FSH level testing is not required for women greater than or equal to 62 years old with 
amenorrhea of greater than or equal to 1 year
NOTE: Women on HRT who still menstruate and women with irregular menses should be 
considered as WOCBP
Women of childbearing potential and all male subjects must be counseled on and understand the 
requirements to avoid pregnancy, as well as acceptable methods of contraception to use 
throughout the study. 
WOCBP with male partners and men with women partners of childbearing potential must use 
two acceptable methods of contraception to avoid pregnancy throughout the study and for up to 
60 days (for WOCBP) and 90 days (for men) after the last dose of IP in such a manner that risk 
of pregnancy is minimized (i.e., this study begins with signed consent form through 60 days (for 
WOCBP) and 90 days (for men) after dosing with study drug). It is required that all WOCBP use 
two methods of contraception for the duration of the study. The two methods should include one 
barrier method (i.e., condom with spermicidal gel, non-hormonal intrauterine devices, cervical 
cap etc.) and one other method. The other method could include hormonal contraceptives (e.g., 
oral contraceptives, injectable contraceptives, patch, or contraceptive implant [e.g., hormonal 
intrauterine device]) used since at least 4 weeks prior to sexual intercourse or another barrier 
method (note, an intrauterine device is considered one method).
Subjects who report abstinence, or who report exclusively being in same-sex relationships are 
still required to understand the contraception requirements in this study to prevent pregnancy. If 
subjects who report abstinence, or who report exclusively being in a same-sex relationship 
engage in heterosexual activity, then the contraception requirements must be followed. 
Males with vasectomy are considered surgically sterile provided the procedure occurred greater 
than 6 months (24) weeks prior to the Screening Visit. Vasectomy is considered one form of 
contraception; therefore, one additional form of contraception must be used to fulfill the 
contraception requirements for the study. Male subjects must not donate sperm until 90 days 
following the last study drug administration.
WOCBP will complete a pregnancy test as outlined in Table 1 and Table 2. If a WOCBP 
suspects that she might be pregnant, she should immediately contact the study doctor.
5.7. Other Restrictions and Precautions (if applicable)
Not Applicable
5.8. Deviation from Inclusion/Exclusion Criteria
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct, 
or study procedures will be documented as a deviation. Deviations will be documented and 
reported through the clinical monitoring of the trial. Deviations will be reported to the IRB/IEC 
at the frequency required by your IRB/IEC. Prospective approval of protocol deviations to 
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recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not 
permitted.
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6. STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES 
6.1. Study Materials
The following study materials will be provided at the study start:

Investigator File/Regulatory Binder

Pharmacy Binder

Drug Accountability Logs

Sample source documents, where applicable

Investigator Brochure

Interactive Web-based Response System (IWRS)

Electronic Case Report Form (eCRF) instructions

Electronic Diary: handheld electronic device (1 will be given to each subject)

Electronic Diary for quality of life scales 

Paper copies of the C-SSRS

Instructions for the eDiary device and access to the portal

Paper diary to record study drug, standard of care migraine medications and rescue 
medications

Paper diary to record menstrual period information (WOCBP)

Laboratory Kits and Laboratory Manual

Back-up forms for CT SAE report, Exposure During Pregnancy (EDP) and Pregnant Partner 
Release Information
All sites will use an Electronic Data Capture (EDC) tool to submit study data to the contract 
research organization (CRO). Electronic Case Report Forms (eCRFs) will be prepared for all 
data collection fields including Serious Adverse Events (SAE) Reporting. SAE data (including 
queries) will be submitted to the CRO using SAE forms. 
The eDiary will be used daily to record migraine occurrence, migraine pain features and 
associated symptoms, and use of acute migraine medication. The eDiary will be used at select 
visits to assess MSQoL v2.1, MIDAS, and EQ-5D-5L. Any assessment completed by the subject 
in the eDiary will be transferred from the site/subject to the vendor and from the vendor to the 
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CRO and Sponsor. No additional source documents are required for scales and assessments 
completed by the subject on the eDiary.
Safety laboratory, plasma, and serum instructions for all specimens collected will be provided by 
a designated central laboratory.
6.2. Safety Assessments
6.2.1. Vital Signs and Physical Measurements (Height and Weight)
Vital signs, weight will be recorded at the scheduled visits as outlined in Table 1 and Table 2.
Height will be recorded at Screening visit only.
Vital signs will include body temperature, respiratory rate, sitting arterial systolic and diastolic 
blood pressure, pulse rate and heart rate. 
6.2.2. Electrocardiogram (ECG)
A standard 12-lead ECG will be recorded during the Screening Visit and at all scheduled visits as 
outlined in Table 1 and Table 2. The investigator will determine if any ECG abnormalities are 
clinically significant or not (see Section 16.4 APPENDIX 4).
6.2.3. Physical Exam 
Subjects will undergo a routine physical examination during the Screening Visit and at all 
scheduled visits as outlined in Table 1 and Table 2. Physical examination includes examination 
of heart, abdomen, lungs, and neurologic system with review of any other system to be guided by 
symptoms.
6.2.4. Laboratory Assessments 
The investigator must review all laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF (see 
guidance in Section 8.2.2). The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition.
All laboratory tests with abnormal values considered to be clinically significant during 
participation in the study should be repeated until the values return to normal or baseline or are 
no longer considered clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a reasonable period of time as judged by 
the investigator, the etiology should be identified, and the sponsor notified.
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual, Table 1 and Table 2.
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If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study management or are considered clinically 
significant by the investigator (e.g., SAE or AE or dose modification), then the results must be 
recorded in the CRF.
6.2.4.1. Safety Laboratory Testing
Blood and urine samples will be obtained as outlined in Table 1 and Table 2 for clinical 
laboratory evaluations. A central laboratory vendor will be utilized for this study and a 
laboratory manual will be provided to each site. If possible, subjects should be fasting for a 
minimum of 8 hours before laboratory tests. However, if a subject is not fasting at a given 
visit, the blood draw should still be performed, and the non-fasting status should be documented.
Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count (WBC) with 
differential, and platelets.
Chemistry: Sodium, potassium, chloride, bicarbonate, calcium; glucose, HbA1c, BUN (urea), 
serum creatinine, uric acid, LDH, total protein, albumin, creatine kinase (CK). 
LFTs: AST, ALT, Alkaline Phosphatase and Bilirubin (Total, Direct, Indirect). Additional tests 
may be obtained to evaluate laboratory abnormalities and/or adverse events; please refer to the 
Laboratory manual.
After Baseline Visit:
Elevations in CK (>5 x ULN) may have further CK fractionation tests performed through the 
central lab  
Elevations in AST/ALT [≥3 × ULN in subjects with AST/ALT baseline value within normal 
range; AST or ALT ≥2 times the baseline values AND ≥3 × ULN, or ≥8 × ULN (whichever is 
smaller) in subjects with AST or ALT baseline values above the normal range] or T bili 
[≥2 × ULN in subjects with T bili baseline value within normal range with no evidence of 
hemolysis and an alkaline phosphatase value <2 × ULN or not available; T bili level increased 
from baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN (whichever is 
smaller) in subjects with T bili baseline values above the normal range] may have reflex to 
gamma-glutamyltransferase (GGT), HAV antibody (HAVIgM), Hepatitis B Surface Antigen 
(HBsAg), Hepatitis B Core Antibody (HBcIgM) and Hepatitis C Antibody (HCVAb)
Lipid panel: Cholesterol, LDL, HDL, triglycerides 
eGFR: eGFR will be calculated and reported by the central lab
Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, protein, 
glucose, and blood. If blood, protein or leukocytes are positive and the result determined 
clinically significant by the investigator, then the subject should be asked to return for an 
unscheduled visit for microscopic examination.
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Urine Drug Screen: For drugs of abuse.
FSH: For WOCBP at screening, to determine WOCBP status.
Additional tests may be obtained to evaluate laboratory abnormalities and/or adverse events; 
please refer to the Laboratory Manual.
6.2.4.2. Pregnancy Testing
WOCBP will complete pregnancy tests (serum and / or urine) at specified study visits, prior to 
taking study drug, and as outlined in Table 1 and Table 2.
6.2.5. Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide 
assessment14. The C-SSRS “Screening version” will be used at the Screening Visit and the “Since 
Last Visit” version”15 will be used at subsequent visits in this study.
The C-SSRS Assessment is intended to help establish a person’s immediate risk of suicide. The 
C-SSRS is a clinician administered scale that should be administered by a certified rater. This 
scale will be collected on site with a paper form. The C-SSRS should be reviewed by the 
Investigator or designee before the subject is allowed to leave the site.
At the Screening Visit, the recall period for completing is 12 months for suicidal ideation and 10 
years for suicidal behavior; at all other visits, the recall period for completing the C-SSRS is 
since the last visit.
Any “Yes” responses must be immediately evaluated by the investigator. If the Investigator 
determines that a subject is at risk of suicide, self-harm, appropriate measures to ensure the 
subject’s safety and obtain mental health evaluation must be implemented. In such 
circumstances, the subject must immediately be discontinued from the study. The event should 
be recorded as either an AE or SAE as determined by the Investigator and reported within 24 
hours to the Sponsor.
6.3. Efficacy Assessments
The eDiary will be used daily to record acute migraine medication dosing occurrences (i.e., with 
triptans, ergotamine, or other), and migraine occurrence, and migraine pain features and 
associated symptoms during the Observation Period, Double-blind Treatment Phase, and Open-
label Extension Phase.
6.4. Other Assessments
The eDiary will be used at select visits to assess MSQoL v2.1, MIDAS, and EQ-5D-5L.
6.4.1. Migraine-Specific Quality-of-Life Questionnaire v 2.1
Impact of treatment on subject-reported quality of life will be assessed using the Migraine-
Specific Qualify-of-Life Questionnaire version 2.1 (MSQoL v2.1). The MSQoL v2.1 is a 14-
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item instrument that has been validated in 3 domains: role function - restrictive, role function -
preventive, and emotional function16. 
6.4.2. Migraine Disability Assessment (MIDAS) Questionnaire
The Migraine Disability Assessment (MIDAS) is a retrospective, subject-reported, 5-item 
questionnaire that measures headache-related disability as lost days due to headache from paid 
work or school, household work and non-work activities over a 3-month period17. 
6.4.3. EQ-5D-5L
EQ-5D-5L is a standardised measure of health status. The EQ-5D-5L consists of 2 pages – the 
EQ-5D-5L descriptive system and the EQ Visual Analogue scale (EQ VAS)18.
The descriptive system comprises the 5 dimensions (mobility, self care, usual activities, 
pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The EQ VAS records the 
respondent’s self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 
‘the best health you can imagine’ and ‘the worst health you can imagine’.
6.5. Early Discontinuation from the Study
Subjects MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Exclusionary laboratory abnormality identified on the Randomization / Baseline Laboratory 
Report  

Pregnancy 

Termination of the study by Pfizer Inc.

Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Poor compliance with study procedures and visits, including poor completion compliance 
with reports in eDiary. 

Subjects with less than 24 completed eDiary reports during the Observation Period will 
not be considered for participation due to non-compliance with the eDiary. 
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
Subjects in the Double-blind Treatment Phase will be monitored closely for compliance 
with the eDiary and may not be considered for the Open-label Extension Phase based on 
PI and / or Sponsor discretion if compliance is low. Subjects who demonstrate poor 
compliance will be discussed with the Sponsor and corrective training will be completed 
by the site with the subject.

During the Open-label Extension Phase, subjects with 6 or more missed reports in the 
eDiary and 3 or more missed dosing entries per month for 2 months (sequential or non-
sequential months) should be considered for discontinuation from the study for poor 
compliance, after discussion with Sponsor. Month is defined as 4 weeks for the purpose 
of this protocol.

Please see Section 6.2.5 for guidance on study discontinuation based on results from the 
C-SSRS.
All subjects who discontinue or who do not enter the Open-label Extension Phase should comply 
with protocol specified End of Treatment procedures as outlined in Table 2. The only exception 
to this requirement is when a subject withdraws consent for all study procedures or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness).
6.5.1. Lost to Follow Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the subject wishes to and/or should continue in the study.

Before a subject is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record.

Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study.
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7. STUDY DRUG MANAGEMENT
7.1. Description of Study Drug
7.1.1. Investigational Product
An IP, also known as investigational medicinal product in some regions, is defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
In this protocol, IP is/are: rimegepant 75 mg and the matching placebo
7.1.2. Packaging, Shipment and Storage
Study drug will be packaged in blistered packaging, which is heat sealed into a wallet. The 
product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature and light) as determined by the sponsor. Please see the 
Pharmacy Manual/Investigator Brochure for specific conditions. If concerns regarding the 
quality or appearance of the study drug arise, do not dispense the study drug and contact the 
sponsor/CRO immediately.
7.2. Dose and Administration
7.2.1. Method of Assigning Subject Identification
Immediately after written informed consent is obtained and before performing any study-related 
procedures, the site staff must obtain a subject identification by adding a new subject in the 
appropriate study-related system. In this study, an IWRS system will be utilized for obtaining 
subject identification. The subject number must not be reused for any other subject in the study. 
Subjects will maintain their subject number assigned at screening throughout the study except in 
cases of re-screening, where permitted, in which case a new subject number must be assigned. 
At the Baseline Visit, eligible subjects will be randomized in a 1:1 ratio to the rimegepant or 
placebo treatment groups. The randomization will be stratified by the use of prophylactic 
migraine medications (yes or no). It is important to correctly enter subjects who are using 
prophylactic migraine medication in the IWRS system. Once a subject is stratified in the 
IWRS, this cannot be changed and will be considered a protocol deviation if later found to 
be entered incorrectly.
After confirming subject eligibility, registering a subject for Baseline (Randomization) will 
trigger a container number for the study drug. The study drug will be dispensed at baseline and 
as needed at the study visits. 
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7.2.2. Selection and Timing of Dose and Administration
Study drug (rimegepant or matching placebo) will be assigned via the IWRS system. There are 
no dose adjustments in this study and subjects will receive rimegepant or placebo in wallets. 
Subjects will be dispensed study drug at the Baseline Visit, and the subjects will be instructed 
that they must take 1 ODT every other calendar day, regardless of whether they have a 
migraine on that day or not. This is the scheduled dosing regimen for the Double-blind 
Treatment Phase and the Open-label Extension Phase. The ODT should be placed on top of or 
under the tongue until fully dissolved then swallowed. Subjects should be instructed to use dry 
hands when handling the study drug.
During the Open-label Extension Phase only, if a subject has a migraine on a non-scheduled 
dosing day, they may take 1 ODT of study drug as acute treatment for their migraine, if needed, 
with a maximum of 1 ODT of study drug per calendar day. This regimen of scheduled dosing on 
every other calendar day and as needed study drug dosing should be followed for up to 40 weeks 
in the Open-label Extension Phase. Subjects can take a maximum of 1 ODT of study drug per 
calendar day for 40 weeks during the Open-label Extension Phase.
Dosing should occur around the same time every other day for migraine prevention. It is 
preferred that subjects dose every other day in the morning; however, it is more important that 
the subject consistently dose at approximately the same time every other day. The time of dosing 
should be consistent throughout the study for the every other day dosing days. If the subject has a 
migraine on a day when they already took study drug, the subject can take their rescue 
medication in accordance with protocol restrictions. 
Subjects must be instructed that they CANNOT take more than 1 ODT of study drug every other 
day during the Double-blind Treatment Phase. Subjects must be instructed to continue taking 
study drug every other calendar day during the Open-label Extension Phase. As noted above, 
subjects may treat a migraine with study drug on a non-scheduled dosing day, but subjects must
be instructed that during the Open-label Extension Phase, they CANNOT take more than 1 ODT 
of study drug per calendar day.
7.2.3. Dose Modifications
There will be no dose adjustments in this study.
7.2.4. Dose Interruptions
If a subject experiences an AE that requires interruption in study drug, the investigator should 
consult with the Sponsor medical monitor to evaluate the need for any additional tests prior to re-
starting study drug.
7.3. Blinding and Unblinding
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the IP is critical to the 
subject’s management, the blind for that subject may be broken by the treating physician.
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Before breaking the blind of an individual subject’s treatment, the Investigator should have 
determined that the information is necessary, (i.e., that it will alter the subject’s immediate 
management). In many cases, particularly when the emergency is clearly not IP related, the 
problem may be properly managed by assuming that the subject is receiving active product 
without the need for unblinding.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind for remaining site personnel.
Sponsor, investigators and subjects will be blinded until the timing of PCD clinical study report 
(CSR), which will occur after the last subject completes the Week 12 visit (Section 9.4).
7.4. Treatment Compliance
Responsible study personnel will dispense the study drug. Subjects should finish a wallet of 
study drug before starting a new wallet. Accountability and compliance verification should be 
documented in the subject’s study records. 
Subjects must be counseled on the importance of taking the study drug as directed (see 
Section 7.2.2). Treatment compliance, review of study drug doses and through review of 
returned study drug, should be assessed by site staff at each study visit. Discrepancies between 
doses reported in the diary, review of study drug and information provided by subject must be 
documented in the source record. Incorrect or missing dosing data and migraine data that are 
reported in the diary will be corrected through either a Data Clarification Record or a Medication 
Reconciliation Form. Investigators should inform subjects that involuntary termination from the 
study will occur in cases where non-compliance is identified. Study staff should contact a subject 
in between the monthly study visits if the subject demonstrates non-compliance with the eDiary 
and document the contact in the source, to identify potential lost to follow up subjects as early as 
possible. 
Investigators must monitor subjects for possible cases of abuse of study drug (subjects taking 
study drug for non-therapeutic purposes, e.g., for psychoactive effects such as high or euphoria). 
Investigators should also assess study drug accountability discrepancies (e.g., missing study 
drug, loss of drug, or non-compliance cases in which more study drug was used, as compared to 
expected). Investigators should obtain more information and explanation from subjects when 
there are study drug accountability discrepancies. See Section 8.1.1.
Cases of potential study drug abuse or overdose (including cases of non-compliance with study 
drug dosing instructions or subjects who discontinue treatment without returning study drug) 
should be documented in the source record and reported as an AE or SAE as appropriate. Dosing 
errors (e.g., accidentally taking 2 ODTs in one calendar day) should be reported as deviations.
Compliance with study intervention will be defined as:

≥80% (and ideally, up to 100%) of study-supplied intervention from Day 1 
through the Treatment Phase are expected to be consumed.
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
Post randomization, at each dispensation visit (refer to Table 1 and Table 2), 
subjects who are <80% compliant must be re-educated on the importance of daily 
self-administration of study intervention.

Overall aim: maintain ≥80% compliance over the duration of dosing with 
randomized study intervention.
7.5. Destruction and Return of Study Drug
All unused and/or partially used study drug can be sent to the predetermined drug destruction 
facility only after being inspected and reconciled by the responsible Study monitor or the 
sponsor’s designee. If it is site policy to destroy study drug on site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the disposal, procedures for proper 
disposal have been established according to the applicable regulations, guidelines and 
institutional procedures, and appropriate records of the disposal have been documented. The 
unused study drugs can only be destroyed after being inspected and reconciled by the responsible 
Study Monitor or the Sponsor’s designee.
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8. ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a subject or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding for example) symptom, or disease temporally associated with the 
use of the IP, whether or not considered relate to the IP. 
Adverse events can be spontaneously reported or elicited during an open-ended questioning, 
examination, or evaluation of a subject. In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.
If a specific diagnosis or syndrome is identified by the Investigator, this should be recorded as 
the AE, rather than recording (as separate AEs) the individual signs/symptoms or clinically 
significant laboratory abnormalities known to be associated with, and considered by the 
Investigator to be a component of, the disease/syndrome. 
Definition of  terms related to all Adverse Events (serious and non-serious):
Mild: Is usually transient and may require only minimal treatment or therapeutic intervention. 
The event does not generally interfere with usual activities of daily living.
Moderate: Is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject.
Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention.
Life threatening: An AE is life threatening if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal.
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery 
for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If 
anything untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria.
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Assessment for Determining Relationship of AE to Study Drug:
The relatedness of each AE to study drug must be classified based on medical judgement and 
according to the following categories. The definitions are as follows:
Related: This category applies to AEs that are considered, with a high degree of certainty, to be 
related to the study drug. An AE may be considered related when it follows a temporal sequence 
from the administration of study drug, it cannot reasonably be explained by the known 
characteristics of the subject’s clinical state, environment, or toxic factors, or other modes of 
therapy administered to the subject. An AE may be considered related when it follows a known 
pattern of response to the study drug, or if the AE reappears upon re-challenge.
Possibly related (non-serious AEs only): This category applies to AEs that are considered to have 
an unlikely connection to study drug, but a relationship cannot be ruled out with certainty.
Unlikely related (non-serious AEs only): This category applies to AEs that do not follow a 
reasonable temporal sequence from the administration of the study drug. The AE may readily 
have been produced by the subject’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the subject.
Unrelated: This category applies to AEs that are considered with a high degree of certainty to be 
due only to extraneous causes (e.g., subject’s clinical state, environment, toxic factors, disease 
under study, etc.) and does not meet the criteria of other categories above.
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious Adverse 
Events (AEs). Subjects should be instructed to notify the Investigator when a Serious Adverse 
Event occurs.
8.1. Serious Adverse Events
8.1.1. Definition of Serious Adverse Event (SAE)
An SAE is any event that meets any of the following criteria at any dose:

Death

Life-threatening

Inpatient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a subject who received rimegepant

Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
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they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such events are (but not limited to):

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias or convulsions that do not result in inpatient hospitalization

Development of drug dependency or drug abuse

Potential drug induced liver injury (see Section 8.4)

Abuse or Overdose of medication
▪
Potential study drug abuse (including cases of excessive non-compliance with study 
drug dosing instructions or subjects who discontinue treatment without returning 
study drug) should be documented in the source record and reported as an AE or SAE 
as appropriate. Investigators must monitor subjects for possible cases of abuse of 
study drug (subjects taking study drug for non-therapeutic purposes, e.g., for 
psychoactive effects such as high or euphoria). Investigators should obtain more 
information and explanation from subjects when there are study drug accountability 
discrepancies
▪
Potential study drug overdose is defined in Section 8.3
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious.
The following hospitalizations are not considered SAEs in Pfizer clinical studies (but may be 
considered non-serious AEs):

A visit to the emergency room or other hospital department <24 hours that does not result in 
an admission (unless considered “important medical event” or event that is life threatening);

Elective surgery planned prior to signing consent;

Admissions as per protocol for a planned medical/surgical procedure;

Routine health assessment requiring admission (i.e., routine colonoscopy);

Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
circumstances).
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Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life functions.
8.1.2. Collection and Reporting Serious Adverse Events
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures. All SAEs must be collected that occur from the time the ICF is 
signed throughout the course of the study up to and including the 2-Week Follow-up Safety 
Visit. The investigator should report any SAE occurring after this time period that is believed to 
be related to study drug or protocol-specific procedures. 
All SAEs should be followed to resolution or stabilization.
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the investigator believes that an SAE is not related to the study drug, but is potentially related 
to the conditions of the study (such as a withdrawal of previous therapy or a complication related 
to study procedure), the relationship should be specified in the narrative section of the SAE 
Report. 
SAEs, whether related or not related to study drug, overdose (see Section 8.3), potential drug 
induced liver injury (see Section 8.4) and pregnancies (see Section 8.5.1) must be reported 
within 24 hours of the Investigator becoming aware of the event. For this study, SAEs will be 
captured through electronic data capture (EDC) and on the SAE report.
The Investigator is responsible for submitting all applicable events to the Independent Review 
Board (IRB) and/or the head of the institutional site as per the IRB’s reporting requirements. 
Additionally, the Investigator, or designated staff, is responsible for entering the SAE 
information into the Case Report Form (CRF) and safety reporting system (i.e., event term, 
start/stop dates, causality, and severity). 
The Investigator is responsible for reporting all SAEs and all Other Important Medical Events to 
the Pfizer Drug Safety Unit (DSU) within 24 hours of learning of the event. 
Any serious adverse event must be reported immediately or no later than 24 hours after 
awareness of the event to Pfizer DSU either via the Pfizer SAE Submission Assistant (PSSA) 
tool or as a written description using the Pfizer CT SAE report form, that must be sent by 
facsimile (fax or eFax), or email to the Pfizer DSU on 0120-442-370 or 03-5309-9061. If only 
limited information is initially available, follow-up reports are required. If an ongoing SAE 
changes in its intensity or relationship to study drug or if new information becomes available, a 
follow-up SAE report should be sent within 24 hours of the Investigator becoming aware of the 
updated information using the same procedure used for the transmission of the initial SAE and 
the same event term should be used.
The minimum information required for an initial SAE report is:
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
Sender of report (Site number, Investigator name)

Subject identification (subject number)

Protocol number

SAE term (if an SAE is being reported)
8.2. Non-serious Adverse Events
A non-serious adverse event is an AE not classified as serious. 
8.2.1. Collection and Reporting of Non-Serious Adverse Events
The collection of non-serious AE information should begin from signing the ICF through the 2-
Weeks Follow up Safety Visit. Non-serious adverse events should be followed until conclusion 
or stabilization, or reported as SAEs if they become serious. Follow-up is also required for non-
serious AEs that cause interruption or discontinuation of study drug or those that are present at 
the end of study treatment. 
8.2.2. Laboratory Test Abnormalities
The following laboratory test abnormalities should be captured on the non-serious AE CRF page 
or SAE Report Form (paper or electronic) as appropriate:
1. Any laboratory test result that is clinically significant or meets the definition of an SAE;
2. Any laboratory abnormality that required the subject to have the study drug discontinued or 
interrupted;
3. Any laboratory abnormality that required the subject to receive specific corrective therapy.
8.3. Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important as determined by the investigator. 
Overdose is reportable to Pfizer Safety only when associated with an SAE. Details of any signs 
or symptoms and their management should be recorded including details of any treatments 
administered.
Asymptomatic dosing errors (e.g., accidentally taking two ODTs instead of prescribed dose of 
1 ODT in one calendar day) should be reported as deviations.
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8.4. Potential Drug Induced Liver Injury (DILI)
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt are 
termed “adaptors.” In some subjects, transaminase elevations are a harbinger of a more serious 
potential outcome. These subjects fail to adapt and therefore are “susceptible” to progressive and 
serious liver injury, commonly referred to as DILI. Subjects who experience a transaminase 
elevation above 3 × ULN should be monitored more frequently to determine if they are 
“adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the 
same laboratory sample). In rare instances, by the time T bili elevations are detected, AST/ALT 
values might have decreased. This occurrence is still regarded as a potential DILI. Therefore, 
abnormal elevations in either AST OR ALT in addition to T bili that meet the criteria outlined 
below are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury have 
been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions. Subjects who present with the following 
laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) cases to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For subjects with baseline AST OR ALT OR T bili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
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The subject should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include 
laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law cases, 
additional laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, 
PT/INR, eosinophils (%), and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further testing, 
as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such as 
review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated product in 
prescription or over the counter medications), recreational drug, or supplement (herbal) use and 
consumption, family history, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and potential occupational 
exposure to chemicals, should be collected. Further testing for acute hepatitis A, B, C, D, and E 
infection, total bile acids, liver imaging (eg, biliary tract), and collection of serum samples for 
acetaminophen/paracetamol drug and/or protein adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no other 
reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) cases are 
to be reported as SAEs, irrespective of availability of all the results of the investigations 
performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology.
8.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a subject receives 
unplanned direct contact with or exposure to the study intervention. Such exposure may or may 
not lead to the occurrence of an AE or SAE. Persons at risk for environmental exposure include 
healthcare providers, family members, and others who may be exposed. An environmental 
exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety within 
24 hours of investigator awareness.
8.5.1. Exposure During Pregnancy
If, following the Baseline Visit it is subsequently discovered that a study subject is pregnant or 
may have been pregnant at the time of the IP exposure, including during at least 6 half-lives after 
the product administration, the IP will be permanently discontinued in an appropriate manner 
(i.e., dose tapering if necessary for subject safety).  Protocol-required procedures for study 
discontinuation and follow-up must be performed on the subject unless contraindicated by the 
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pregnancy (i.e., x-ray studies).  Other appropriate pregnancy follow-up procedures should be 
considered if indicated.  
Sites should instruct subjects to contact the Investigator if they become pregnant during the 
course of the study. The investigator must immediately notify the Pfizer Medical Monitor (or 
designee) and report the event by either using the CT SAE Report Form or via PSSA tool and by 
completing an Exposure During Pregnancy (EDP) Supplemental Form following the SAE 
reporting procedures as described in Section 8.1.2. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable offspring information must also be reported on an EDP 
Supplemental Form.
Any pregnancy that occurs in a female partner of a male study subject should be reported to the
Pfizer DSU.  Information on this pregnancy will be collected on an EDP Supplemental Form, as 
appropriate.   
An EDP occurs if:

A female subject is found to be pregnant while receiving or after discontinuing study 
intervention. 

A male subject who is receiving or has discontinued study intervention inseminates a female 
partner. 

A female non-subject is found to be pregnant while being exposed or having been exposed to 
study intervention because of environmental exposure. Below are examples of environmental 
EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion or skin contact then inseminates his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to termination 
of pregnancy). 

If EDP occurs in a subject/subject’s partner, the investigator must report this information to 
Pfizer Safety using the CT SAE Report Form or via PSSA, regardless of whether an SAE has 
occurred. Details of the pregnancy will be collected after the start of study intervention and 
until 66 hours after the last dose. 
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
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form or via PSSA. Since the exposure 
information does not pertain to the subject enrolled in the study, the information is not 
recorded on a CRF; however, a copy of the completed report is maintained in the investigator 
site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are conclusive 
for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets the 
criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an intrauterine 
fetal demise, or a neonatal death), the investigator should follow the procedures for reporting 
SAEs. Additional information about pregnancy outcomes that are reported to Pfizer Safety as 
SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported as an 
SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further follow-up of 
birth outcomes will be handled on a case by case basis (eg, follow-up on preterm infants to 
identify developmental delays). In the case of paternal exposure, the investigator will provide the 
subject with the Pregnant Partner Release of Information Form to deliver to his partner. The 
investigator must document in the source documents that the subject was given the Pregnant 
Partner Release of Information Form to provide to his partner.
8.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female subject is found to be breastfeeding while receiving or after discontinuing 
study intervention. 

A female non-subject is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie., environmental exposure). An example of 
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environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion.  
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported using 
the CT SAE Report Form or via PSSA. When EDB occurs in the setting of environmental 
exposure, the exposure information does not pertain to the subject enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed report is maintained in 
the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in breastfeeding 
women (eg, vitamins) is administered in accordance with authorized use. However, if the infant 
experiences an SAE associated with such a drug, the SAE is reported together with the EDB.
8.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form or PSSA, regardless of 
whether there is an associated SAE. Since the information about the occupational exposure does 
not pertain to a subject enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed report is maintained in the investigator site file.
8.6. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.  
8.7. Medication Errors
Medication errors may result from the administration or consumption of the study intervention 
by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form or PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
8.8. Adverse Events of Special Interest
Not applicable for this study.
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9. STATISTICS
Complete details on the statistical methods for this study may be found in the Statistical Analysis 
Plan (SAP).
9.1. Sample Size
The study will randomize roughly 245 subjects per treatment arm to obtain roughly 225 
evaluable subjects per treatment arm.
With a sample size of roughly 490 subjects randomized, and 245 subjects per group, we expect 
roughly 225 evaluable subjects per group in the double-blind treatment migraine analysis set. 
Assuming rimegepant provides roughly a 1 day advantage over placebo on the primary endpoint, 
and a common standard deviation of 3.75 days, then the study will have roughly 80% power on 
the primary endpoint at a 2-sided alpha level of 0.05. The estimates for the change in migraine 
days per month and the standard deviation are consistent with publicly available information 
from another investigational oral CGRP antagonist for this indication.
9.2. Analysis Set 
The following analysis sets will be used in this study:

Enrolled: Subjects who sign the informed consent form and are assigned a subject 
identification number by the IWRS.

Full: Subjects in the enrolled analysis set who were assigned a randomized treatment group 
by IWRS. 

Safety: subjects in the enrolled analysis set who take ≥1 dose of study drug (double-blind or 
open-label).

Double-blind treatment safety: Subjects in the safety analysis set who take 1 dose of 
double-blind study drug (rimegepant or placebo).

Open-label rimegepant safety: Subjects in the safety analysis set who take 1 dose of 
open-label rimegepant.

Double-blind or open-label rimegepant safety: Subjects in the safety analysis set who 
take 1 dose of double-blind or open-label rimegepant.

Follow-up safety: subjects in the safety analysis set whose last contact date is in the 
follow-up safety analysis period.

Double-blind treatment efficacy: Subjects in the full analysis set who are randomized only 
once and take 1 dose of double-blind study drug.
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
Double-blind treatment migraine: Subjects in the double-blind treatment efficacy 
analysis set with 14 days of eDiary data (not necessarily consecutive) in both the 
Observation Period and 1 month (4-week interval) during the Double-blind Treatment 
Phase.

Double-blind treatment first month migraine: subjects in the double-blind treatment 
efficacy analysis set with 24 days of eDiary efficacy data (not necessarily consecutive) 
in both the OP and in first month (4-week interval) of the Double-blind Treatment Phase.

Open-label rimegepant efficacy: subjects in the double-blind treatment efficacy analysis 
set who take 1 dose of open-label rimegepant.
9.3. Statistical Methods
The Observation Period represents “baseline” for endpoints based on migraine days.
9.3.1. Primary Endpoint(s)
The primary endpoint will be assessed for the double-blind treatment migraine analysis set using 
a linear mixed effects model with repeated measures that will  include the following variables: 
change from baseline (i.e., Observation Period) in the number of migraine days per month as the 
dependent variable;  baseline number of migraine days per month (i.e., in the Observation 
Period) as a covariate; and fixed effects for treatment group, randomization stratum (i.e., 
prophylactic migraine medication use), month, and month-by-treatment group interaction. 
Migraine days are of any pain intensity. Months are defined using 4-week intervals as Month 1 
(Weeks 1 to 4), Month 2 (Weeks 5 to 8), and Month 3 (Weeks 9 to 12). The number of migraine 
days per month is prorated to 28 days to account for days with missing migraine data. The 
difference estimate (rimegepant – placebo), standard error (SE), 95% confidence interval (CI), 
and p-value will be reported for the last 4 weeks (i.e., Month 3).
The repeated measures error structure is assumed to be constant across treatment groups, and 
will be initially specified as unstructured. If the model fails to converge or cannot be fit with an 
unstructured error structure, then a heterogeneous Toeplitz error structure will be attempted. If 
the Toeplitz fails, then an autoregressive order 1 error structure will be attempted.
The Huber-White robust “sandwich” estimator will be used for the estimation of SEs, which 
does not require constant response variances between treatment groups and different baseline 
covariate values. 
9.3.2. Secondary Endpoint(s)
The proportion of subjects with 50% reduction from baseline in the number of moderate or 
severe migraine days per month in the last 4 weeks (Weeks 9 to 12) of the Double-blind 
Treatment Phase will be analyzed using a Mantel-Haenszel risk estimation with stratification by 
randomization stratum for the double-blind treatment migraine analysis set. Missing data are 
imputed as non-response (i.e., failure). The stratified difference estimate (rimegepant – placebo), 
SE, 95% CI, and p-value will be reported.
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The mean change from baseline in the number of migraine days per month over the entire 
Double-blind Treatment Phase (Weeks 1 to 12) will be assessed for the double-blind treatment 
migraine analysis set with the same model used for the primary endpoint. 
The mean change from baseline in the number of migraine days per month in the first 4 weeks 
(Weeks 1 to 4) of the Double-blind Treatment Phase will be assessed for the double-blind 
treatment migraine analysis set with the same model used for the primary endpoint.
The mean number of acute migraine-specific medication days per month in the last 4 weeks 
(Weeks 9 to 12) of Double-blind Treatment Phase will be assessed for the double-blind treatment 
migraine analysis set using a model that is similar in structure to that used for the primary 
endpoint, except that the number of acute migraine-specific medication days per month is the 
dependent variable and there is no covariate. Acute migraine-specific medications are triptans 
and ergotamine.
The mean changes from baseline in MSQoL role function - restrictive domain score, MIDAS 
total score, and EQ-5D-5L VAS score at Week 12 will be assessed for the double-blind treatment 
efficacy analysis set using linear models that will  include the following variables: Week 12 
change from baseline in the score as the dependent variable; baseline score as a covariate; and 
fixed effects for treatment group and randomization stratum. The Week 12 difference estimate 
(rimegepant – placebo), SE, 95% CI, and p-value will be reported for each endpoint.
See Section 9.3.4 for safety endpoints.
9.3.3. Multiplicity Correction
Type I error will be controlled by using a hierarchical gate keeping procedure. First, the 
significance of the primary endpoint will be evaluated at a 2-sided alpha level of 0.05. If the 
primary endpoint is significant, then secondary endpoints 1 through 7 will be tested in the order 
in which they appear in the Section 3.2. Testing will stop at the first non-significant secondary 
endpoint. If the primary endpoint is not significant, then any further tests on secondary endpoints 
1 through 7 will have p-values presented only for descriptive purposes.
9.3.4. Analysis of Safety
Deaths will be listed regardless of onset for the enrolled analysis set.
The frequencies of safety endpoints will be assessed descriptively as the number and percentage 
of subjects with events/findings separately for the 3 safety analysis sets.
The frequencies of the following safety endpoints will be tabulated on treatment: AEs by 
intensity (mild, moderate, severe, total); AEs by relationship to study drug (related, possibly 
related, unlikely related, not related); SAEs; AEs leading to study drug discontinuation; hepatic-
related AEs by intensity; hepatic-related AEs leading to study drug discontinuation; grade 3 to 4 
laboratory test abnormalities; and LFT elevations based on fold changes above ULN, including 
ALT or AST >3 × ULN concurrent (on the same laboratory test collection date) with T bili
>2 × ULN.
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The investigators will determine the intensity of AEs and the relationship of AEs to study drug. 
The investigators’ terms will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) available at the start of the study. AEs will be tabulated by 
system organ class and preferred term. In tables by intensity, if a subject has an AE with 
different intensities over time, then only the greatest intensity will be reported. In tables by 
relationship to study drug, if a subject has an AE with different relationships over time, then the 
highest degree of relatedness to study drug will be reported.
Laboratory test results will be graded according to numeric laboratory test criteria in Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (2017), if available. Otherwise, 
if CTCAE grades are not available, then results will be graded according to numeric laboratory 
test criteria in Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Corrected Version 2.1 (2017). 
In addition, Quality Tolerance Limits (QTLs) are predefined parameters that are monitored 
during the study. Important deviations from the QTLs and any remedial actions taken will be 
summarized.
9.4. Schedule of Analyses
There are 3 planned database locks: (1) primary completion date (PCD) database lock for the 
PCD clinical study report (CSR), which will occur after the last subject completes the Week 12 
Visit; (2) Week 24 database lock for the Week 24 CSR, which will occur after the last subject 
completes the Week 24 Visit, if requested by a regulatory agency; and (3) last subject last visit 
(LSLV) database lock for the LSLV CSR, which will occur after the last subject completes the 
Follow-up Week 2 Visit. The content of the analyses in each CSR will be documented in the 
Statistical Analysis Plan (SAP).
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10. ETHICS AND RESPONSIBILITIES
10.1. Good Clinical Practice
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP), International Conference on Harmonization guidelines, and all 
applicable regulations, including the Federal Food, Drug and Cosmetic Act, U.S. applicable 
Code of Federal Regulations (title 21), any Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) requirements relative to clinical studies. The study will also be conducted 
in compliance with the recommendations laid down in the most recent version of the Declaration 
of Helsinki. 
This study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
The Sponsor is responsible for ensuring that all updated relevant information related to the 
protocol be submitted to regulatory authorities and Independent Ethics Committees in 
accordance with local laws and regulations. This includes expedited reporting of suspected 
unexpected serious adverse reactions per regulatory guidelines.
In the event of any prohibition or restriction imposed (ie., clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken 
by the investigator to protect the study participants against any immediate hazard, and of any 
serious breaches of this protocol or of the ICH GCP guidelines that the investigator becomes 
aware of.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
10.2. Data and Safety Monitoring Committee
This study will not make use of a Data and Safety Monitoring Committee. Rimegepant has been 
found to be well tolerated in previous clinical studies and post-marketing in the U.S. Safety will 
be closely monitored via the sites and procedures for unblinding in cases of emergency will be 
followed.
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10.3. Institutional Review Board/Independent Ethics Committee
The Investigators or the head of institutional sites agree to provide the IRB/IEC with all 
appropriate documents, including a copy of the protocol/amendments, ICFs, advertising text (if 
any), Investigator’s brochure (if any) and any other written information provided to study 
subjects. The trial will not begin until the Investigators have obtained the IRB/IEC favorable 
written approvals for the above-mentioned study documents. 
In the event that the protocol is amended, the revised protocol must be approved by the IRB/IEC 
prior to its implementation, unless the changes involve only logistical or administrative aspects 
of the trial. 
10.4. Informed Consent
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
Pfizer (or designee) will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Before the potential subject has undergone any study-related screening procedures, the nature of 
the study and the potential risks associated with it will be explained to the subject, and the 
subject will be given an opportunity to ask questions to his or her satisfaction. After the 
questions are answered, but before proceeding further, the subject must read, sign and date an 
IRB/IEC approved written informed consent form for study. The signed and dated ICF will be 
retained at the Investigator’s site, with a copy provided to the study subject and date will be 
entered in his or her CRF or appropriate system. The IRB/IEC must review and approve all 
protocol versions and informed consent form versions and a copy of each version of the IRB/IEC 
approved protocol and informed consent form is to be retained in the Study Master file. Any 
revisions to the protocol or ICF will be reviewed and approved by the IRB/IEC and subjects will 
be informed of ICF changes and document continuing consent by signing and dating the revised 
version of the ICF.
If a revised ICF is introduced during the study, each subject’s further consent must be obtained. 
The new version of the ICF must be approved by the IRB/IEC, prior to subsequently obtaining 
each subject’s consent. 
If informed consent is initially given by a subject’s legal guardian or legally acceptable 
representative, and the subject subsequently becomes capable of making and communicating 
their informed consent during the study, then the consent must additionally be obtained from the 
subject. 
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The informed consent form must also include a statement that Pfizer and its representatives and 
regulatory authorities may have direct access to subject records. 
10.5. Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed
to record all observations and other data pertinent to the investigation of each study subject. Data 
reported on the CRF that are derived from source documents must be consistent with the source 
documents or the discrepancies must be explained.
Electronic CRFs will be prepared for all data collection fields when EDC is being used. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator must retain a copy of the CRFs including records of changes and corrections. If 
EDC is being used, signatures will be obtained electronically and a copy of the electronic CRFs 
will be provided (or the data from the CRFs) for future reference. 
10.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study or the country in which the study 
was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, regardless of 
the geographical location in which the study is conducted. These results are submitted for 
posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com for 
Pfizer sponsored interventional studies at the same time the corresponding study results are 
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posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable information 
anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included in 
marketing applications. Clinical documents include summary documents and CSRs including the 
protocol and protocol amendments, sample CRFs, and SAPs. Clinical documents will have 
personally identifiable information anonymized.
10.6.1. Data sharing
Pfizer provides researchers secure access to subject level data or full CSRs for the purposes of 
“bonafide scientific research” that contributes to the scientific understanding of the disease, 
target, or compound class. Pfizer will make data from these trials available 18 months after study 
completion. Subject level data will be anonymized in accordance with applicable privacy laws 
and regulations. CSRs will have personally identifiable information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not be 
provided to applicants with significant conflicts of interest, including individuals requesting 
access for commercial/competitive or legal purposes.
10.7. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study contact 
list located in the principal investigator ISF.
To facilitate access to their investigator and the sponsor’s MQI for study related medical 
questions or problems from non-study healthcare professionals, subjects are provided with an 
ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) subject’s study identification number, (c) site emergency phone 
number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number. 
The ECC is intended to augment, not replace, the established communication pathways between 
the subject and their investigator and site staff, and between the investigator and sponsor study 
team. The ECC is only to be used by healthcare professionals not involved in the research study, 
as a means of reaching the investigator or site staff related to the care of a subject. The Pfizer 
Call Center number is to be used when the investigator and site staff are unavailable. The Pfizer 
Call Center number is not for use by the subject directly; if a subject calls that number directly, 
they will be directed back to the investigator site.
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11. RECORDS MANAGEMENT
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the status 
of the study and to review the original documents of the study.
The investigator and/or the head of institutional site must retain all study records and source 
documents for the maximum time period required by the applicable regulations and guidelines, 
or institution procedures or for the period of time specified by the sponsor, whichever is longer. 
The investigator and/or the head of institutional site must contact the Sponsor prior to destroying 
any records associated with this study. 
Pfizer will notify the investigators and/or the head of institutional site when the study files for 
this study are no longer needed. 
If the investigator withdraws from the study (i.e., retirement, relocation), the records shall be 
transferred to a mutually agreed upon designee. Notice of such transfer will be given in writing 
to Pfizer. 
It is the responsibility of the investigator or designee to ensure that the current disposition record 
of IP (may be supplied by the sponsor) is maintained at each study site where the study drug is 
inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:

amount of study drug received and placed in storage area

label ID number or batch number or Kit number as specified for the protocol

amount dispensed to and returned from each subject

amount transferred to another area or site for dispensing or storage if applicable

amount of drug lost or wasted

amount destroyed at the site if applicable

amount returned to sponsor, if applicable

retain samples for bioavailability/bioequivalence, if applicable

record of dates and initials of personnel responsible for IM dispensing and accountability   
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11.1. Source Documentation
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent for all subjects on study. 
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical records for each subject for verification of data points,  
unless otherwise instructed by the Sponsor or designee to enter data directly on the eCRF.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
11.2. Study Files and Record Retention
The Sponsor does not require original documents that have already been scanned and entered 
into the eTMF system to be forwarded to the Sponsor. Any original documents (e.g., signed 
financial disclosure, signed ICF, etc.) will be retained in the regulatory binder at the study site. 
The CRO will conduct a final TMF reconciliation to ensure all study files and regulatory 
documents have been correctly uploaded to the TMF prior to the close or termination of the 
study. Any materials or documents to support the clinical trial outside of the eTMF (i.e., training
materials) should be maintained by the CRO. The Sponsor will be contacted to determine 
whether the study documents/materials that are retained outside of the TMF will be forwarded to 
the Sponsor, destroyed or kept at the CRO or at another facility for a longer period of time at the 
Sponsor’s expense.
The CRO will maintain adequate study records after completion or termination of study. After 
that period, the Sponsor will be contacted to determine whether the study records will be 
forwarded to the Sponsor, destroyed or kept at CRO or at another facility for a longer period of 
time at the Sponsor’s expense.
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12. AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Pfizer (or specified designee). A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately. Any permanent change to the 
protocol must be handled as a protocol amendment. The written amendment must be submitted 
to the IRB/IEC and the investigator must await approval before implementing the changes. Pfizer 
or specified designee will submit protocol amendments to the appropriate regulatory authorities 
for approval.
If in the judgment of the IRB/IEC, the investigator, and/or Pfizer, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the subject and/or has 
an impact on the subject’s involvement as a study subject, the currently approved written 
informed consent form will require similar modification. In such cases, informed consent will be 
renewed for subjects enrolled in the study before continued participation.
13. PUBLICATIONS POLICY
The publication policy of Pfizer is discussed in the investigator’s Clinical Research Agreement.
14. STUDY DISCONTINUATION 
Both Pfizer and the Principal Investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, Pfizer or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Principal Investigator will inform the IRB/IEC of the same. In 
terminating the study, Pfizer and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests.
15. DATA PROTECTION
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of subject data.
Subjects’ personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized study 
staff have access. The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster. In the event 
of a potential personal data breach, the study site will be responsible for determining whether a 
personal data breach has in fact occurred and, if so, providing breach notifications as required by 
law.
To protect the rights and freedoms of subjects with regard to the processing of personal data, 
subjects will be assigned a single, subject specific numerical code. Any subject records or data 
sets that are transferred to the sponsor will contain the numerical code; subject names will not be 
transferred. All other identifiable data transferred to the sponsor will be identified by this single, 
subject specific code. The study site will maintain a confidential list of subjects who participated 
in the study, linking each subject’s numerical code to their actual identity and medical record ID. 
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In case of data transfer, the sponsor will protect the confidentiality of subjects’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
When subject data are to be deleted, the investigator will ensure that all copies of such data are 
promptly and irrevocably deleted from all systems.
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16. APPENDICES
16.1. APPENDIX 1 – Inhibitors and Inducers of CYP3A4 and Inhibitors of P-glycoprotein 
(Not all-inclusive)
The following medications and medication combinations are moderate to strong inhibitors of 
CYP3A4. This list should not be considered all-inclusive. As described in the study protocol, 
concomitant use of moderate to strong CYP3A4 inhibitors is prohibited. Individual drug labels 
should be reviewed for specific information on propensity to cause moderate to strong inhibition 
of the CYP3A4 enzyme for a specific compound.
Strong CYP3A4 inhibitors
Boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, 
indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and 
ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, clarithromycin, nefazodone, 
nelfinavir, mifepristone, mibefradil.
Moderate CYP3A4 inhibitors
Amprenavir, aprepitant, casopitant, cimetidine, ciprofloxacin, diltiazem, dronedarone, 
erythromycin, fluconazole, Seville orange, isavuconazole, lefamulin, letermovir, netupitant, 
ravuconazole, verapamil
The following medications and supplements are moderate to strong inducers of CYP3A4. As 
described in the study protocol, concomitant use of moderate to strong CYP3A4 inducers is 
prohibited. This list should not be considered all-inclusive. Individual product labels should be 
reviewed for specific information on propensity to cause moderate to strong induction of the 
CYP3A4 enzyme for a specific compound.
Strong CYP3A4 inducers
Carbamazepine, phenytoin, rifampin, St. John’s Wort, rifapentine, phenobarbital, apalutamide
Moderate CYP3A4 inducers
Bosentan, rifabutin, modafinil, nafcillin, efavirenz, etravirine, lopinavir
The following medications are strong P-glycoprotein (P-gp) inhibitors. As described in the study 
protocol, concomitant use of strong P-gp inhibitorsis prohibited. This list should not be 
considered all-inclusive. Individual product labels should be reviewed for specific information 
on propensity to strongly inhibit P-gp for a specific compound.
Strong P-gp Inhibitors
Amiodarone, clarithromycin, cyclosporine, dronedarone, itraconazole, lapatinib, propafenone, 
quinidine, ritonavir, verapamil
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Resources: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
DrugInterac/ucm093664.htm#table3-2
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
DrugInteracti/ucm093664.htm#table3-3
Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: the 
University of Washington Metabolism and Transport Drug Interaction Database. Hum 
Genomics. 2010 Oct;5(1):61-72.
University of Washington Metabolism and Transport Drug Interaction Database accessible at 
https://www.druginteractioninfo.org/
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16.2. APPENDIX 2 – Definition of Migraine Days
Migraine Day: Any calendar day in which the subject experiences a qualified migraine 
headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine 
headache is defined as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting at 
least one of the following criteria (a and/or b)
a.
≥ 2 of the following pain features:

Unilateral location,

Pulsating quality (throbbing),

Moderate or severe pain intensity,

Aggravation by or causing avoidance of routine physical activity (e.g., walking or 
climbing stairs)
b. ≥ 1 of the following associated symptoms:

Nausea and/or vomiting

Photophobia and phonophobia
If the subject took a migraine-specific medication (i.e., study drug, triptan or ergotamine) during 
aura or to treat headache on a calendar day, then it will be counted as a migraine day regardless 
of the duration and pain features/associated symptoms. The use of study drug on non-scheduled 
dosing days is only permitted during the Open-label Extension Phase; dosing with study drug 
on non-scheduled dosing days is not permitted during the Double-blind Treatment Phase.
A moderate to severe migraine day is a migraine day with a migraine reported with moderate or 
severe pain intensity.
Headache Day: Any calendar day in which the subject experiences a qualified headache (initial 
onset, continuation, or recurrence of the headache). A qualified headache is defined as:

a qualified migraine headache (including an aura-only event that is treated with acute 
migraine-specific medication), or

a qualified non-migraine headache, which is a headache that lasts ≥ 30 minutes and is 
not a qualified migraine headache, or

a headache of any duration for which acute headache treatment is administered.
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Acute Migraine-specific Medication Treatment Day: Any calendar day during which the 
subject took a migraine-specific medication (i.e., study drug, triptan or ergotamine). The use of 
study medication on non-scheduled dosing days is only permitted during the Open-label 
Extension Phase; dosing with study drug on non-scheduled dosing days is not permitted 
during the Double-blind Treatment Phase.
Monthly eDiary Data: Data collected by the eDiary based on the subject’s monthly IP dosing 
schedule when at least 14 days of eDiary data are collected within that interval. Monthly 
frequency measurements will be prorated to 28-day equivalents.
Migraine Attack: An episode of any qualified migraine headache. The following rules will be 
used to distinguish an attack of long duration from two attacks, or to distinguish between attacks 
and relapses:
a.
A migraine attack that is interrupted by sleep, or temporarily remits, and then recurs 
within 48 hours (i.e., ≤ 48 hours between the start of the migraine attack to the time of the 
recurrence) will be considered as one attack and not two.
b. An attack treated successfully with medication but with relapse within 48 hours (i.e., ≤ 48 
hours between the start of the migraine attack to the time of the recurrence) will be 
considered as one attack.
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16.3. APPENDIX 3 – Categories of Migraine Prevention Medications
No therapeutic response with > 2 of the following 8 medication categories for prophylactic 
treatment of migraine after an adequate therapeutic trial. These medication categories are:

Category 1: Divalproex sodium, sodium valproate

Category 2: Topiramate, carbamazepine, gabapentin

Category 3: Beta blockers (for example: atenolol, bisoprolol, metoprolol, nadolol, nebivolol, 
pindolol, propranolol, timolol)

Category 4: Tricyclic antidepressants (for example: amitriptyline, nortriptyline, 
protriptyline)

Category 5: Serotonin-norepinephrine reuptake inhibitors (for example: venlafaxine, 
desvenlafaxine, duloxetine, milnacipran)

Category 6: Flunarizine, Lomerizine, verapamil

Category 7: Angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker 
(ARB): (for example: lisinopril, candesartan)

Category 8: Botulinum toxin injections: (for example: Botox®[onabotulinumtoxinA])
No therapeutic response is defined as no reduction in headache frequency, duration, or severity 
after administration of the medication for at least 6 weeks at the generally-accepted therapeutic 
dose(s) based on the investigator’s assessment.
The following scenarios do not constitute lack of therapeutic response:

Lack of sustained response to a medication

Failure to tolerate a therapeutic dose
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16.4. APPENDIX 4 - ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New‑onset atrial flutter or fibrillation, with controlled ventricular response rate: ie.,
rate <120 bpm.

New‑onset type I second‑degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF >450 ms AND QTcF change from baseline >60 ms.

New ST‑T changes suggestive of myocardial ischemia.

New‑onset LBBB (QRS complex >120 ms).

New‑onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia. 

Asystole

In awake, symptom‑free subjects in sinus rhythm, with documented asystolic 
pauses ≥3 seconds or any escape rate <40 bpm, or with an escape rhythm that is 
below the AV node;

In awake, symptom‑free subjects with atrial fibrillation and bradycardia with 1 or 
more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate >120 
bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short duration 
with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 second duration, including idioventricular rhythm (HR <40 
bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as torsades 
de pointes]).

Type II second‑degree (Mobitz II) AV block.

Complete (third‑degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30-second duration).

Second‑ or third‑degree AV block requiring pacemaker placement.
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
Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications from 
the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-inclusive of 
what is to be reported as AEs/SAEs.
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16.5. APPENDIX 5 – Protocol Amendment History
Version Number
Brief Description Summary of Changes
Date
Version 1.0 – Original 
Not Applicable
04-Apr-2022
Version 2.0
Updated Section 2.2, 2.3, Secondary Objectives and 
Exploratory Objectives: EQ-5D-5L related objectives 
modified.
Updated Section 3.2, 3.3, Secondary Endpoints and 
Exploratory Endpoints: EQ-5D-5L related endpoints 
modified.
Updated Section 5.2, Inclusion Criteria: inclusion criteria 
2g clarified. 
Updated Section 5.3, Exclusion Criteria: exclusion 
criteria 1a reworded. 
Updated Section 5.4, Prohibited and Restricted 
Concomitant Medications: Traditional Chinese 
Medicines and Lasmiditan added.
Corrected inconsistencies and typographical errors 
throughout the protocol.
30-Aug-2022
Version 3.0
Updated Section 2.2, 2.3, Secondary Objectives and 
Exploratory Objectives: Reversed the order of secondary 
objectives 3 and 4 based on results from migraine-
prevention study BHV3000-305. Modified language 
around objectives to align with more recent BHV3000 
migraine prevention studies. Added efficacy exploratory 
objectives to align with more recent BHV3000 migraine 
prevention studies.
Updated Section 3, Study Endpoints: Provided 
clarifications where the endpoints data are derived from.
Updated Section 3.2, 3.3, Secondary Endpoints and 
Exploratory Endpoints: Modified language to align with 
changes to secondary and exploratory objectives.
Added Section 6.4 Other Assessments: Moved previous 
Sections 6.3.1 through 6.3.3 about MSQoL, MIDAS, and 
EQ-5D-5L) here. Specified the use of the eDiary.
Updated Section 9, Statistics: Modified language to align 
with more recent BHV3000 migraine prevention studies.
Provided clarifications throughout the protocol.
Corrected inconsistencies and typographical errors 
throughout the protocol.
29-Nov-2022
Version 4.0
Updated Section 4.3, Schedule of Assessments: 
administrative letter 01 issued in Jan 2023 incorporated. 27-Feb-2023
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Updated Section 4.3.1.1, Screening Visit: Provisions 
added which permit re-screening of those who were 
screen failures previously.
Updated Section 5.3, Exclusion Criteria: exclusion 
criteria 1a, 1c, 2i, 2o, 2p, 5f, 5g and 5i modified.
Updated Section 5.4, Prohibited and Restricted 
Concomitant Medications: #8 and 18 modified.
Updated Section 5.5, Prophylactic and Rescue 
Medications: valproic acid/valproate added as a 
prophylactic medication; revision to upper limit of 
acetaminophen dose from 1000 mg/day to 2000 mg/day.
Update Section 6.2.4.1, Safety Laboratory Testing:
administrative letter 01 issued in Jan 2023 incorporated.
Updated Section 8.1.2, Collection and Reporting Serious 
Adverse Events: immediate notification to the Medical 
Monitor no longer required.
Provided clarifications throughout the protocol.
Corrected inconsistencies and typographical errors 
throughout the protocol.
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17. REFERENCES
1. Sakai F, Igarashi H. Prevalence of migraine in Japan: a nationwide survey. Cephalalgia 
1997;17:15-22.
2. Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new target in the 
treatment of headache. Cephalalgia 2004;24:611-22.
3. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play 
a causative role in migraine. Cephalalgia 2002;22:54-61.
4. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral 
circulation of humans during migraine headache. Annals of neurology 1990;28:183-7.
5. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies 
characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Annals of 
neurology 1993;33:48-56.
6. Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. BIBN4096BS antagonizes human 
alpha-calcitonin gene related peptide-induced headache and extracerebral artery dilatation. 
Clin Pharmacol Ther 2005;77:202-13.
7. BHV3000-303-CSR. A Phase 3, Double-blind, Randomized, Placebo-controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT) for the Acute 
Treatment of Migraine. Biohaven Pharmaceuticals, Inc 2019.
8. BHV3000-302-CSR. A Phase 3, Double-blind, Randomized, Placebo-controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) for the Acute Treatment of Migraine. Biohaven 
Pharmaceuticals, Inc 2019.
9. BHV3000-301-CSR. A Phase 3, Double-blind, Randomized, Placebo-controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) for the Acute Treatment of Migraine. Biohaven 
Pharmaceuticals, Inc 2019.
10. CN170003-CSR. A Phase 2b, adaptive, double-blind, randomized, multi-center outpatient, 
dose-ranging trial to evaluate the efficacy and safety of BMS-927711 for the acute treatment 
of moderate or severe migraine. Bristol-Myers Squibb Company 2013.
11. BHV3000-201-Final-CSR. A Multicenter, Open-label, Long-term Safety Study of BHV-
3000 in the Acute Treatment of Migraine. Biohaven Pharmaceuticals, Inc 2020.
12. BHV3000-305 Addendum 01 to CSR. A Phase 2/3, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Efficacy and Safety of Rimegepant in Migraine Prevention. 
Biohaven Pharmaceuticals, Inc 2022.
13. Headache Classification Committee of the International Headache Society (IHS) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
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14. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168:1266-77.
15. Posner K BD, Lucas C, et al. Columbia-Suicide Severity Rating Scale.  January 14, 2009.
16. Martin BC, Pathak DS, Sharfman MI, et al. Validity and reliability of the migraine-specific 
quality of life questionnaire (MSQ Version 2.1). Headache 2000;40:204-15.
17. Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument assessing 
migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache 
2001;41:854-61.
18. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16:199-208.
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