Clinical trial NCT05399459
Conditions: Migraine
Keywords: Migraine Headache Acute Migraine
Sponsor: Pfizer
Start date: 2022-08-09; Completion date: 2024-01-19
Enrollment: 897 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to determine the appropriate dose of rimegepant in Japanese subjects, as well as to evaluate the efficacy, safety, and tolerability of rimegepant in Japanese subjects for the acute treatment of migraine.

Detailed description:

Arms: arm 1: Single dose of 25 mg orally disintegrating tablet of rimegepant arm 2: Single dose of 75 mg orally disintegrating tablet of rimegepant arm 3: Matching placebo tablet
Interventions: intervention 1: Rimegepant 25 MG intervention 2: Rimegepant 75 MG intervention 3: Placebo
Intervention descriptions: intervention 1: Single dose of 25 mg orally disintegrating tablet of rimegepant intervention 2: Single dose of 75 mg orally disintegrating tablet of rimegepant intervention 3: Matching placebo tablet

Protocol documents:
Prot_000.pdf: 
Study BHV3000-313 (C4951022) Clinical Protocol, Version 4.0
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DRUG:
BHV-3000 (PF-07899801) (rimegepant)
STUDY NUMBER(S):
BHV3000-313 (C4951022)
PROTOCOL TITLE:
Double-Blind, 
Randomized, 
Placebo-Controlled, 
Dose-Ranging Study to Evaluate the Efficacy and 
Safety of Rimegepant for the Acute Treatment of 
Migraine in Japanese Subjects
IND NUMBER:
N/A
EudraCT NUMBER:  
(if applicable)
N/A
ClinicalTrials.gov ID:
NCT05399459
SPONSOR:
Pfizer Inc.
66 Hudson Boulevard East New York, NY 10001
ORIGINAL PROTOCOL DATE:
04-Apr-2022
VERSION NUMBER:
4.0
VERSION DATE:
03-Aug-2023
BRIEF TITLE:
Efficacy and Safety Study of Rimegepant for the 
Acute Treatment of Migraine in Japanese Subjects 
(Japan Only)
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 4.0 (03 August 2023)
Overall Rationale for the Amendment: Change in the statistical method; change in 
sponsorship from Biohaven to Pfizer
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Changed hypothesis testing 
strategy. Formal hypothesis testing 
will be conducted for rimegepant 
75 mg at a 2-sided alpha level of 
0.05. No formal hypothesis testing 
will be conducted for rimegepant 
25 mg.
Considering the overall clinical 
development strategy on 
rimegepant in Japan, formal 
hypothesis testing for rimegepant 
25 mg compared with placebo is 
confirmed not necessary in this 
study.
9.3.2 Primary Endpoint(s)
9.3.4 Multiplicity Correction
Referenced study number 
BHV3000-313 to C4951022 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
Removed the exclusion criterion 
for patients with HIV disease.
Aligned with rimegepant 
prescribing information where 
there is no exclusion for use in 
patients with HIV.
5.3 Exclusion Criteria #2a)
Changed exclusion criterion for 
liver enzymes (ALT and AST) to 
>2.0 × ULN.
Aligned with rimegepant 
prescribing information where 
there is no exclusion for subjects 
with mild hepatic disease.
5.3 Exclusion Criteria #5g)
Removed specific exclusionary 
ECG criteria
Allowed for investigator opinion 
on exclusionary ECG findings.
5.3 Exclusion Criteria #5d), 5e)
Changed GFR from 40 to 30 
ml/min/1.73m2.
Allowed for subjects with 
moderate renal impairment to be 
included in the trial consistent 
with the prescribing information.
5.3 Exclusion Criteria #5a)
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 #7h)
Removed exclusion criterion for 
“m.  Hematologic or solid 
Exclusion criterion already 
covered in another Exclusion 
criterion (#2j) and to align with 
5.3 Exclusion Criteria #2m)
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malignancy diagnosis within 5 
years prior to screening”.
rimegepant prescribing 
information where there is no 
contraindication for use.
Updated exclusion criterion for 
illicit drug use.
Updated prohibited and restricted 
concomitant medications 
accordingly.
Prohibited illicit drug use meeting 
DSM-V criteria for substance use 
disorder within 6 months of 
screening.
5.3 Exclusion Criteria #2l)
5.4 Prohibited and Restricted 
Concomitant Medications #13
Removed exclusion criterion for 
“l. positive drug screen for drugs 
of abuse”.
Exclusion criterion already 
covered in another Exclusion 
criterion (#2k) and to align with 
rimegepant prescribing 
information where there is no 
contraindication for use.
5.3 Exclusion Criteria #2l)
Allowed for rescreening of 
subjects due to prior failed 
eligibility criteria.
Allowed for rescreening of 
subjects who previously were 
screen failed for an amended 
exclusionary criterion.
4.3.1 Screening Phase (3-28 days)
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 #22
Removed tacrolimus from the 
Strong CYP3A4 inhibitors list. 
Removed grapefruit juice from the 
Moderate CYP3A4 inhibitors list.
Aligned with nonclinical and 
clinical drug-drug interaction 
(DDI) information available on 
rimegepant.
16.1 Appendix 1 – Inhibitors and 
Inducers of CYP3A4 and 
Inhibitors of P-glycoprotein (Not 
all-inclusive)
Updated potential 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. Laboratory Testing
8.4 Potential Drug Induced Liver 
Injury (DILI)
Added Appendix for ECG 
findings of Potential Clinical 
Concern.
Aligned with Pfizer protocol 
template.
16.2 Appendix 2 – ECG Findings 
of Potential Clinical Concern
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 definition of analysis 
sets.
Aligned with Statistical Analysis 
Plan.
9.2 Analysis Set
Clarified/corrected statistical 
methods.
Provided corrections or 
clarifications. Aligned with
Statistical Analysis Plan.
9.3.1 Demographic and Baseline 
Characteristics 
9.3.2 Primary Endpoint(s)
9.3.3 Secondary Endpoint(s)
Updated the analysis of safety.
Aligned with Statistical Analysis 
Plan.
9.3.5 Analysis of Safety
Clarified/corrected the objectives 
and endpoints.
Clarifications and corrections to 
provide more appropriate 
wordings. Aligned with Statistical 
Analysis Plan.
2. Study Objectives
3. Study Endpoints
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Changed End of Treatment Visit 
window to +4 days.
Allowed flexibility.
4.3. Schedule of Assessments
4.3.4. End of Treatment
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
Updated text for Data Protection.
Aligned with Pfizer protocol 
template.
15 Data Protection
Deleted paper adverse event (AE)
logs.
Clerical correction.
6.1. Study Materials
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 the publication policy.
Updated in alignment with the 
change in sponsorship.
13. Publications Policy
Added 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
Updated Section 8.3. Overdose. 
Overdose is reportable to Pfizer 
Safety only when associated with 
an SAE.
8.3. Overdose
Moved prior Protocol Amendment 
Summary of Changes to 
Appendix.
Editorial.
16.3 Appendix 3 Protocol 
Amendment History
Updated List of abbreviations.
Editorial.
List of Abbreviations
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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: Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Study to 
Evaluate the Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine in Japanese 
Subjects
Brief Title: Efficacy and Safety Study of Rimegepant for the Acute Treatment of Migraine in 
Japanese Subjects (Japan Only)
Regulatory Agency Identification Number(s):
US IND Number:
NA
EudraCT Number:
NA
ClinicalTrials.gov ID:
NCT05399459
Pediatric Investigational Plan Number:
NA
Protocol Number:
BHV3000-313 (C4951022) Version 4.0
Phase:
2/3
Rationale: Rimegepant is being developed for the treatment of migraine. Effectiveness as an 
acute treatment for migraine was demonstrated in a Phase 2b double-blind, randomized, placebo-
controlled, dose-ranging study that compared rimegepant at doses of 10, 25, 75, 150, 300 and 
600 mg to placebo (CN170003 study). In this study, rimegepant at 75 mg showed efficacy on all 
4 traditional endpoints: pain, nausea, photophobia and phonophobia. The primary endpoint was 
pain freedom at 2 hours post-dose. In this study the 10 and 25 mg doses did not separate from 
placebo. The 75, 150 and 300 mg doses were significantly better than placebo and showed 
similar efficacy. The efficacy of the 600 mg dose was somewhat less than that of the 75, 150 and 
300 mg doses, but was still better than that of placebo.
In the United States, the 75 mg dose was selected as the optimal dose and tested against placebo 
in 3 pivotal studies for the acute treatment of migraine. The efficacy of the 75 mg dose was 
confirmed in all 3 studies.
This study is being conducted to determine the appropriate dose of rimegepant in Japanese 
subjects, as well as to evaluate the efficacy, safety, and tolerability of rimegepant in Japanese 
subjects for the acute treatment of migraine.
Since the optimal dose in the US has been demonstrated to be 75 mg and the 25 mg dose is 
included in the study to permit an assessment of the dose response for rimegepant in Japanese 
subjects, formal hypothesis testing compared with placebo will be restricted to rimegepant 75 mg 
arm.
Primary Objectives: 
To compare the efficacy of rimegepant 75 mg with placebo in the acute treatment of migraine in 
Japanese subjects.
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Secondary Objectives:

To compare the efficacy of rimegepant 75 mg with placebo in the acute treatment of 
migraine in Japanese subjects on the following secondary endpoints:

Pain relief at 2 hours post-dose.

Freedom from the Most Bothersome Symptom (MBS) associated with migraine at 2 
hours post-dose.

The ability to function normally at 2 hours post-dose

Sustained pain relief from 2 to 24 hours post-dose

Rescue medication use within 24 hours of initial treatment

Sustained pain relief from 2 to 48 hours post-dose

Freedom from photophobia at 2 hours post-dose

Sustained pain freedom from 2 to 24 hours post-dose

Freedom from phonophobia at 2 hours post-dose

Sustained pain freedom from 2 to 48 hours post-dose

Freedom from nausea at 2 hours post-dose

Pain relapse from 2 to 48 hours post-dose

To compare the efficacy of rimegepant 25 mg with placebo in the acute treatment of 
migraine in Japanese subjects on the same efficacy endpoints

To evaluate the tolerability and safety of rimegepant 75 mg and 25 mg in the acute 
treatment of migraine
Primary Endpoint:
Pain freedom at 2 hours post-dose will be assessed using the percentage of subjects that report no 
pain at 2 hours post-dose. Pain will be measured on a 4-point Likert scale (0=none, 1=mild, 
2=moderate, 3=severe).
Secondary Endpoints:

Pain relief at 2 hours post-dose will be assessed using the percentage of subjects that 
report a pain intensity level of none or mild at 2 hours post-dose. 
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
Freedom from the most bothersome symptom (MBS) at 2 hours post-dose will be 
assessed using the percentage of subjects with an MBS reported before dosing that is 
absent at 2 hours post-dose. The MBS before dosing will be reported as nausea, 
phonophobia, or photophobia. Symptom status will be reported post-dose as present or 
absent for each symptom (nausea, phonophobia, and photophobia).

Ability to function normally at 2 hours post-dose will be assessed using the percentage of 
subjects with a functional disability level of normal at 2 hours post-dose in the subset of 
subjects with functional disability at the time of dosing. Functional disability level will be 
measured on a 4-point numeric rating scale (0=normal, 1=mildly impaired, 2=severely 
impaired, 3=requires bedrest), and functional disability will be defined as mildly 
impaired, severely impaired, or requires bedrest.

Sustained pain relief from 2 to 24 hours post-dose will be assessed using the percentage 
of subjects with pain intensities of none or mild from 2 to 24 hours post-dose.

Rescue medication use within 24 hours post-dose will be assessed using the percentage of 
subjects that take rescue medication within 24 hours after administration of study 
medication (rimegepant or placebo).

Sustained pain relief from 2 to 48 hours post-dose will be assessed using the percentage
of subjects with pain intensities of none or mild at all time points from 2 to 48 hours 
post-dose.

Freedom from photophobia at 2 hours post-dose will be assessed using the percentage of 
subjects with photophobia absent at 2 hours post-dose in the subset of subjects with 
photophobia present at the time of dosing.

Sustained pain freedom from 2 to 24 hours post-dose will be assessed using the 
percentage of subjects with pain intensities of none at all time points from 2 to 24 hours 
post-dose. 

Freedom from phonophobia at 2 hours post-dose will be assessed using the percentage of 
subjects with phonophobia absent at 2 hours post-dose in the subset of subjects with 
phonophobia present at the time of dosing.

Sustained pain freedom from 2 to 48 hours post-dose will be assessed using the 
percentage of subjects with pain intensities of none at all time points from 2 to 48 hours 
post-dose.

Freedom from nausea at 2 hours post-dose will be assessed using the percentage of 
subjects with nausea absent at 2 hours post-dose in the subset of subjects with nausea 
present at the time of dosing.

Pain relapse from 2 to 48 hours post-dose will be assessed using the percentage of 
subjects with a pain intensity of mild, moderate, or severe at any time point after 2 hours 
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through 48 hours post-dose in the subset of subjects with pain freedom at 2 hours post-
dose.

Tolerability and safety will be evaluated by the percentage of subjects with AEs by 
intensity, SAEs, and grade 3 to 4 laboratory test abnormalities.
Overall Design:
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of rimegepant 75 mg as compared to placebo in the treatment of moderate or severe migraine in 
Japanese subjects. The investigational product will be rimegepant at a 25 mg or 75 mg dose level 
or a matching placebo. The 25 mg rimegepant dose is included in the study to permit an 
assessment of the dose response for rimegepant in Japanese subjects.
A subject whose usual migraine attack results in headache pain of moderate or severe intensity 
and who is otherwise found acceptable for entry into this trial based on inclusion and exclusion 
criteria will first participate in the screening phase (3 – 28 day period). Subjects on prophylactic 
migraine medication are permitted to remain on therapy provided they have been on a stable 
dose for at least 3 months prior to study entry.
After randomization, the subject will be dispensed a single dose of the double-blind study 
medication that will be taken at the time a migraine attack reaches moderate or severe pain 
intensity (described below) on the numeric rating scale (NRS) as indicated in the electronic diary 
(eDiary). The subject will be instructed to take their study medication, as an outpatient, when (if) 
they have a migraine headache which reaches moderate or severe pain intensity and only after 
they have identified their most bothersome migraine-associated symptom (phonophobia, 
photophobia or nausea). The subject will complete an eDiary for up to 48 hours after taking 
study medication. The subject will contact the study center immediately if they should 
experience any AEs. Subjects will record efficacy data in their eDiary. This includes the 
following: onset time of headache, intensity of the headache prior to and at the time of taking 
study medication. The subject should record all headache intensity leading up to dosing, but 
should not dose with study medication until the headache reaches moderate or severe pain 
intensity. Headache severity will be recorded using a 4-point numeric rating scale (no pain, mild 
pain, moderate pain, severe pain) at the onset of the migraine and after dosing at time points of 
15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 8, 24 and 48 hours. The presence or absence of 
associated symptoms (nausea, photophobia, phonophobia) and ratings of functional disability 
(4-point scale: normal, mildly impaired, severely impaired, requires bedrest) will be recorded at 
the same time points as the headache severity ratings. Subjects who experience reduction of 
headache pain to a mild intensity or pain free intensity level will be considered to have achieved 
pain relief. The subject who does not experience relief of their migraine headache at the end of 
2 hours after dosing with study drug (and after the 2-hour assessments have been completed on 
the eDiary) will be permitted to use the following rescue medication: aspirin, ibuprofen, 
acetaminophen (up to 2000 mg/day), naproxen (or any other type of nonsteroidal anti-
inflammatory drug (NSAID)), antiemetics (e.g., metoclopramide), or baclofen. These are the 
only medications allowed for rescue treatment after 2 hours post dose of study drug. If at the end 
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of 48-hours after dosing with study drug (but before the End of Treatment Visit) subjects are in 
need of migraine relief, they may take their prescribed standard of care medications, including 
triptans if not contraindicated, provided all of the assessments have been completed on the 
eDiary.  Exclusionary rescue medication such as opioids, ergotamines, butalbital compounds, 
and muscle relaxants (except baclofen as a rescue medication, see above) are not allowed during 
this study. Similarly, if the migraine is relieved by study drug at 2 hours after dosing but then 
recurs to a moderate or severe intensity level between 2 and 48 hours, the subject will be 
permitted to take the same rescue therapy as outlined above. In all circumstances, the subject will 
always continue to complete their eDiary for up to 48 hours after taking the study drug.
Number of Subjects:
Approximately 1220 subjects will be screened to randomize up to approximately 795 subjects 
(265 per arm). Subjects will be randomized in a 1:1:1 ratio to the rimegepant 25 mg, rimegepant 
75 mg, or placebo treatment groups. The randomization will be stratified by the use of 
prophylactic migraine medications (yes or no).
Study Population:
The study will recruit subjects 18 years of age and older with at least a 1-year history of 
migraines (with or without aura), consistent with a diagnosis according to the International 
Classification of Headache Disorders, 3rd edition, including an age of onset prior to 50, migraine 
attacks that last about 4 - 72 hours, not more than 8 attacks of moderate or severe intensity per 
month within the last 3 months and not less than 2 attacks per month.
Statistical Methods:
This study will randomize a total of 795 subjects in a 1:1:1 ratio to rimegepant 25 mg, 
rimegepant 75 mg, or placebo. It is anticipated that this will result in approximately 750 subjects 
in efficacy analysis set, with roughly 250 subjects in each treatment arm. The sample size for this 
study was initially designed to provide 80% power to test each of the 2 rimegepant doses against 
placebo at a Bonferroni corrected 2-sided alpha level of 0.025 using a chi-square test. Although 
testing strategy is changed in Protocol version 4.0 and formal hypothesis testing will no longer 
be conducted for rimegepant 25 mg, the original sample size will remain as it is.  The sample 
size estimate was based on historical data from pivotal study BHV3000-303, in which the rates 
of pain freedom were 10.9% for placebo and 21.2% for Rimegepant. 
The primary endpoint of pain freedom at 2 hours post-dose will be evaluated using Mantel-
Haenszel risk estimation with stratification by the use of prophylactic migraine medication (yes 
or no). The same statistics for secondary endpoints will be presented as those for the primary 
endpoint.
Safety endpoints will be assessed descriptively.
Ethical Considerations:
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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 for 
the acute treatment of migraine 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. Effectiveness for the preventive treatment of episodic migraine was demonstrated in a 
Phase 2/3 double-blind, randomized, placebo-controlled study of rimegepant 75 mg dosed every 
other day (EOD). Every other day dosing was also well tolerated with no signals of 
hypersensitivity, cardiovascular events, or hepatotoxicity. Every other day scheduled dosing with 
as needed dosing was shown to be well tolerated with a favorable safety profile.
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)..........................................................................................6
STUDY SCHEMATIC ............................................................................................................12
TABLE OF CONTENTS.........................................................................................................13
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................17
LIST OF ABBREVIATIONS..................................................................................................18
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
1.6. Research Hypothesis ...............................................................................................26
2. STUDY OBJECTIVES........................................................................................................27
2.1. Primary Objective(s) ...............................................................................................27
2.2. Secondary Objective(s) ...........................................................................................27
2.3. Exploratory Objective(s) (if applicable) .................................................................27
3. STUDY ENDPOINTS.........................................................................................................28
3.1. Primary Endpoint(s) ................................................................................................28
3.2. Secondary Endpoint(s) ............................................................................................28
3.3. Exploratory Endpoint(s) (if applicable) ..................................................................29
4. STUDY PLAN.....................................................................................................................30
4.1. Study Design and Duration .....................................................................................30
4.2. Study Schematic......................................................................................................30
4.3. Schedule of Assessments ........................................................................................31
4.3.1. Screening Phase (3-28 days).......................................................................36
4.3.2. Randomization Visit/Treatment Phase (Up to 45 days) .............................36
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4.3.2.1. eDiary Data Collections ............................................................36
4.3.3. Extension Phase..........................................................................................37
4.3.4. End of Treatment........................................................................................37
4.4. Post Study Access to Therapy.................................................................................37
5. POPULATION ....................................................................................................................38
5.1. Number of Subjects.................................................................................................38
5.2. Inclusion Criteria.....................................................................................................38
5.3. Exclusion Criteria....................................................................................................39
5.4. Prohibited and Restricted Concomitant Medications..............................................42
5.5. Rescue Medications.................................................................................................43
5.6. Women of Childbearing Potential...........................................................................44
5.7. Other Restrictions and Precautions (if applicable)..................................................45
5.8. Deviation from Inclusion/Exclusion Criteria ..........................................................45
6. STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES........................46
6.1. Study Materials .......................................................................................................46
6.2. Safety Assessments .................................................................................................46
6.2.1. Vital Signs and Physical Measurements (Height and Weight)...................46
6.2.2. Electrocardiogram (ECG)...........................................................................47
6.2.3. Physical Exam ............................................................................................47
6.2.4. Laboratory Assessments.............................................................................47
6.2.4.1. Laboratory Testing ....................................................................47
6.2.4.2. Pregnancy Testing.....................................................................48
6.2.5. Columbia-Suicide Severity Rating Scale (C-SSRS)...................................48
6.3. Efficacy Assessments..............................................................................................49
6.3.1. Pain .............................................................................................................49
6.3.2. Nausea, Phonophobia and Photophobia .....................................................49
6.3.3. Rescue Medication......................................................................................49
6.3.4. Functional Disability ..................................................................................49
6.4. Early Discontinuation from the Study.....................................................................49
6.4.1. Lost to Follow Up.......................................................................................50
7. STUDY DRUG MANAGEMENT......................................................................................50
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7.1. Description of Study Drug ......................................................................................50
7.1.1. Investigational Product ...............................................................................50
7.1.2. Packaging, Shipment and Storage ..............................................................51
7.2. Dose and Administration.........................................................................................51
7.2.1. Method of Assigning Subject Identification...............................................51
7.2.2. Selection and Timing of Dose and Administration ....................................52
7.2.3. Dose Modifications.....................................................................................52
7.3. Blinding and Unblinding.........................................................................................52
7.4. Treatment Compliance ............................................................................................52
7.5. Destruction and Return of Study Drug....................................................................53
8. ADVERSE EVENTS...........................................................................................................54
8.1. Serious Adverse Events...........................................................................................55
8.1.1. Definition of Serious Adverse Event (SAE)...............................................55
8.1.2. Collection and Reporting Serious Adverse Events.....................................56
8.2. Non-serious Adverse Events ...................................................................................57
8.2.1. Collection and Reporting of Non-Serious Adverse Events ........................58
8.2.2. Laboratory Test Abnormalities...................................................................58
8.3. Overdose..................................................................................................................58
8.4. Potential Drug Induced Liver Injury (DILI) ...........................................................58
8.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure..............................................................................................60
8.5.1. Exposure During Pregnancy.......................................................................60
8.5.2. Exposure During Breastfeeding..................................................................62
8.5.3. Occupational Exposure...............................................................................62
8.6. Lack of Efficacy......................................................................................................62
8.7. Medication Errors....................................................................................................62
8.8. Adverse Events of Special Interest..........................................................................63
9. STATISTICS .......................................................................................................................63
9.1. Sample Size.............................................................................................................63
9.2. Analysis Set.............................................................................................................63
9.3. Statistical Methods ..................................................................................................64
9.3.1. Demographic and Baseline Characteristics ................................................64
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9.3.2. Primary Endpoint(s)....................................................................................64
9.3.3. Secondary Endpoint(s)................................................................................64
9.3.4. Multiplicity Correction...............................................................................64
9.3.5. Analysis of Safety.......................................................................................65
9.4. Schedule of Analyses ..............................................................................................65
10. ETHICS AND RESPONSIBILITIES................................................................................66
10.1. Good Clinical Practice ..........................................................................................66
10.2. Data and Safety Monitoring Committee ...............................................................66
10.3. Institutional Review Board/Independent Ethics Committee.................................66
10.4. Informed Consent..................................................................................................67
10.5. Case Report Forms................................................................................................67
10.6. Dissemination of Clinical Study Data...................................................................68
10.6.1. Data sharing..............................................................................................68
10.7. Sponsor’s Medically Qualified Individual ............................................................69
11. RECORDS MANAGEMENT ...........................................................................................70
11.1. Source Documentation ..........................................................................................70
11.2. Study Files and Record Retention.........................................................................71
12. AMENDMENTS ...............................................................................................................72
13. PUBLICATIONS POLICY ...............................................................................................72
14. STUDY DISCONTINUATION ........................................................................................72
15. DATA PROTECTION.......................................................................................................72
16. APPENDICES ...................................................................................................................74
16.1. APPENDIX 1 – Inhibitors and Inducers of CYP3A4 and Inhibitors of P-
glycoprotein (Not all-inclusive) ................................................................................74
16.2. APPENDIX 2 – ECG Findings of Potential Clinical Concern .............................76
16.3. APPENDIX 3 – Protocol Amendment History.....................................................78
17. REFERENCES ..................................................................................................................79
LIST OF TABLES
Table 1
Schedule of Assessments..........................................................................31
Table 2
Treatment Assignment to each group.......................................................52
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LIST OF FIGURES
Figure 1
Study Schematic .......................................................................................30
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AV
Atrioventricular
BHV
Biohaven
bpm
beats per minute
BUN
Blood Urea Nitrogen
CGRP
Calcitonin Gene-Related Peptide
CI
confidence interval
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
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
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EOD
Every Other Day
eTMF
electronic Trial Master File
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1c
HR
heart rate
HRT
hormone replacement therapy
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
identification
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
ISF
investigator site file
IWRS
Interactive Web Response System
kg
Kilogram
L
Liters
LBBB
Left bundle branch block
LFTs
Liver Function Tests
MBS
most bothersome symptom
mg
Milligram
min
Minute
mmHg
Millimeters Mercury
MQI
medically qualified individual
NC=F
Non-completer = Failure
NSAID
Nonsteroidal Anti-inflammatory Drugs
PACL
Protocol Administrative Change Letter
P-gp
P-glycoprotein
PK
Pharmacokinetic
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PRN
Pro re nata, as needed
PSSA
Pfizer SAE Submission Assistant
PVC
Premature ventricular contraction
QTc
Interval between Q-wave and T-wave in the cardiac cycle
QTcF
QTc corrected using Fridericia’s formula
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
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
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 8900 unique subjects have participated in Phase 1 studies in 
healthy subjects or Phase 2 and 3 studies in subjects with migraine; of these, approximately 
6036 unique subjects have received rimegepant at any dose. The clinical pharmacology of 
rimegepant has been well characterized in a comprehensive program based on 27 Phase 1 
studies, including 7 studies that examined the biopharmaceutics of rimegepant. In the 4 Phase 3, 
placebo-controlled studies for the acute treatment, rimegepant administered as a single 75 mg 
dose (either as a tablet or ODT) was well tolerated in adult subjects experiencing migraine 
attacks with moderate to severe intensity and demonstrated a safety profile comparable to 
placebo (2439 rimegepant-treated subjects and 2456 placebo-treated subjects). In total, the 
current data suggests a favorable benefit-risk profile for rimegepant in the acute treatment of 
migraine attacks.
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 
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 
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of future attacks, which are 2 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 DDIs; 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 (MBS) 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 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 + as needed (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 drug-induced liver injury (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. Women of childbearing potential (WOCBP) must have a negative pregnancy 
test and WOCBP and fertile men must use 2 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 
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constipation are reviewed in each aggregate report per Food and Drug Administration (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 Brochure, which is the 
SRSD for this study.
1.5. Study Rationale
Rimegepant is being developed for comprehensive management of migraine. Efficacy of 
rimegepant as an acute treatment of migraine was shown by a phase 2b double-blind, 
randomized, placebo-control, dose-finding clinical study. In this study, rimegepant at 75 mg 
showed efficacy on all 4 traditional endpoints including pain, nausea, photophobia, and 
phonophobia7. Efficacy of rimegepant was confirmed by 3 pivotal phase 3 clinical studies in 
which freedom from pain and freedom from the MBS 2 hours post-dose were the co-primary 
endpoints8,9,10.
Based on these data and long-term safety (for up to 52 weeks) observed in approximately 1,800 
subjects in the open label Study BHV3000-20111, once-daily administration of rimegepant 75 mg 
taken on an as-needed basis was approved as an acute treatment of migraine by the US FDA12. 
Study BHV3000-313 will be conducted to evaluate efficacy, safety, and tolerability of 
rimegepant for acute treatment of migraine in Japanese subjects. This clinical trial will be a 
bridging study to a U.S. dose-finding study (Study CN170003). In addition, efficacy of 
rimegepant in Japanese subjects will be evaluated in the context of the U.S. studies for acute 
treatment of migraine (Study CN170003, Study BHV3000-301, Study BHV3000-302, and Study 
BHV3000-303). Taken together, results of this trial (BHV3000-313) and the results of 4 U.S. 
Studies (3 pivotal phase 3 placebo-controlled clinical studies for acute treatment [Study 
BHV3000-3038, Study BHV3000-3029, and Study BHV3000-30110] and an open-label, long-
term safety study [Study BHV3000-20111]) will enable the benefit/risk assessment of rimegepant 
75 mg for acute treatment of migraine in Japanese subjects.
1.5.1. Study Design Rationale
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of rimegepant as compared to placebo in the treatment of moderate or severe migraine. The study 
is designed to provide data in Japanese subjects that will bridge to the existing comprehensive 
clinical trial data available for rimegepant at a 25 mg and 75 mg dose in the acute treatment of 
migraine. 
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Study BHV3000-313 will demonstrate that rimegepant for the acute treatment of migraine has a 
safety and efficacy profile in Japanese subjects with migraine that is consistent with the profile 
observed in the clinical program to date.
The study drug will be rimegepant formulated in a 25 mg or 75 mg ODT or a matching placebo. 
The subjects will be instructed to take their study drug, as an outpatient, when (if) they have a 
migraine headache which reaches moderate or severe intensity. 
The study will screen approximately 1,220 subjects to allow approximately 795 subjects to be 
randomized. The subjects will be randomized in a 1:1:1 ratio to the rimegepant 25 mg, 75 mg or 
placebo treatment groups. The randomization will be stratified by the use of prophylactic 
migraine medications (yes or no).
This study design is utilized to confirm the efficacy and safety profiles observed in the Phase 2b 
and 3 completed phase 3 studies with rimegepant. Incorporation of placebo and use of 
appropriate rescue medications will permit enrollment of subjects with a broad range of 
comorbidities, including cardiovascular conditions, representative of the potential treatment 
population.
1.5.2. Dose Selection Rationale
Effectiveness of rimegepant as an acute treatment for migraine was demonstrated in CN170003 
study that compared rimegepant at doses of 10, 25, 75, 150, 300 and 600 mg to placebo2. The 
primary endpoint was pain freedom at 2 hours post-dose. In this study the 10 and 25 mg doses 
did not separate from placebo. The 75, 150 and 300 mg doses were significantly better than 
placebo and showed similar efficacy. 
The 75 mg dose was selected as the optimal dose for evaluation in Phase 3 studies for the acute 
treatment of migraine. The efficacy of the 75 mg dose was confirmed in all 3 pivotal studies.
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.
This study is being conducted to determine the appropriate dose of rimegepant in Japanese 
subjects, as well as to evaluate the efficacy, safety, and tolerability of rimegepant in Japanese 
subjects for the acute treatment of migraine.
Since increasing the dose of rimegepant above 75 mg was shown not to increase efficacy in 
study CN170003, this study tests the 75 mg dose of rimegepant against placebo in Japanese 
subjects. The 25 mg dose is being assessed to confirm the dose response in Japanese subjects is 
similar to that observed in the U.S. population in CN170003.
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1.6. Research Hypothesis
Rimegepant 75 mg ODT will have efficacy superior to placebo in the treatment of acutemigraine 
with a favorable safety profile suitable for use by a broad subject population.
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2. STUDY OBJECTIVES
2.1. Primary Objective(s)

To compare the efficacy of rimegepant 75 mg with placebo in the acute treatment of migraine
in Japanese subjects.
2.2. Secondary Objective(s)

To compare the efficacy of rimegepant 75 mg with placebo in the acute treatment of 
migraine in Japanese subjects on the following secondary endpoints:

Pain relief at 2 hours post-dose

Freedom from the MBS associated with migraine at 2 hours post-dose

The ability to function normally at 2 hours post-dose

Sustained pain relief from 2 to 24 hours post-dose

Rescue medication use within 24 hours of initial treatment

Sustained pain relief from 2 to 48 hours post-dose

Freedom from photophobia at 2 hours post-dose

Sustained pain freedom from 2 to 24 hours post-dose

Freedom from phonophobia at 2 hours post-dose

Sustained pain freedom from 2 to 48 hours post-dose

Freedom from nausea at 2 hours post-dose

Pain relapse from 2 to 48 hours post-dose

To compare the efficacy of rimegepant 25 mg with placebo in the acute treatment of 
migraine in Japanese subjects on the same efficacy endpoints

To evaluate the tolerability and safety of rimegepant 75 mg and 25 mg in the acute treatment 
of migraine
2.3. Exploratory Objective(s) (if applicable)
Not Applicable.
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3. STUDY ENDPOINTS 
Subjects who take rescue medication will be classified as failures for all efficacy assessments 
that are reported at or after taking rescue medication. This method will apply to all endpoints 
listed below, except the secondary endpoint of rescue medication use within 24 hours post-dose.
3.1. Primary Endpoint(s)

Pain freedom at 2 hours post-dose will be assessed using the percentage of subjects that 
report no pain at 2 hours post-dose. Pain will be measured on a 4-point Likert scale (0=none, 
1=mild, 2=moderate, 3=severe).
3.2. Secondary Endpoint(s)

Pain relief at 2 hours post-dose will be assessed using the percentage of subjects that report a 
pain intensity level of none or mild at 2 hours post-dose. 

Freedom from the MBS at 2 hours post-dose will be assessed using the percentage of 
subjects with an MBS reported before dosing that is absent at 2 hours post-dose. The MBS 
before dosing will be reported as nausea, phonophobia, or photophobia. Symptom status will 
be reported post-dose as present or absent for each symptom (nausea, phonophobia, and 
photophobia).

Ability to function normally at 2 hours post-dose will be assessed using the percentage of 
subjects with a functional disability level of normal at 2 hours post-dose in the subset of 
subjects with functional disability at the time of dosing. Functional disability level will be 
measured on a 4-point numeric rating scale (0=normal, 1=mildly impaired, 2=severely 
impaired, 3=requires bedrest), and functional disability will be defined as mildly impaired, 
severely impaired, or requires bedrest.

Sustained pain relief from 2 to 24 hours post-dose will be assessed using the percentage of 
subjects with pain intensities of none or mild from 2 to 24 hours post-dose.

Rescue medication use within 24 hours post-dose will be assessed using the percentage of 
subjects that take rescue medication within 24 hours after administration of study medication 
(rimegepant or placebo).

Sustained pain relief from 2 to 48 hours post-dose will be assessed using the percentage of 
subjects with pain intensities of none or mild at all time points from 2 to 48 hours post-dose.

Freedom from photophobia at 2 hours post-dose will be assessed using the percentage of 
subjects with photophobia absent at 2 hours post-dose in the subset of subjects with
photophobia present at the time of dosing.

Sustained pain freedom from 2 to 24 hours post-dose will be assessed using the percentage
of subjects with pain intensities of none at all time points from 2 to 24 hours post-dose. 
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
Freedom from phonophobia at 2 hours post-dose will be assessed using the percentage of 
subjects with phonophobia absent at 2 hours post-dose in the subset of subjects with
phonophobia present at the time of dosing.

Sustained pain freedom from 2 to 48 hours post-dose will be assessed using the percentage
of subjects with pain intensities of none at all time points from 2 to 48 hours post-dose.

Freedom from nausea at 2 hours post-dose will be assessed using the percentage of subjects 
with nausea absent at 2 hours post-dose in the subset of subjects with nausea present at the 
time of dosing.

Pain relapse from 2 to 48 hours post-dose will be assessed using the percentage of subjects 
with a pain intensity of mild, moderate, or severe at any time point after 2 hours through 48 
hours post-dose in the subset of subjects with pain freedom at 2 hours post-dose.

Tolerability and safety will be evaluated by the percentage of subjects with AEs by intensity, 
SAEs, and grade 3 to 4 laboratory test abnormalities.
3.3. Exploratory Endpoint(s) (if applicable)
Not Applicable.
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4. STUDY PLAN
4.1. Study Design and Duration
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of rimegepant 75 mg as compared to placebo in the treatment of moderate or severe migraine. 
The investigational product is formulated as rimegepant 25 mg, rimegepant 75 mg or a matching 
placebo. The 25 mg rimegepant dose is included in the study to permit an assessment of the dose 
response for rimegepant in Japanese subjects. The total duration of the study will be 
approximately 11 weeks. This includes a 3 to 28 day Screening Period, a Treatment Phase that 
can last up to 45 days or until the subject has a migraine that reaches moderate or severe 
intensity, followed by an End of Treatment Visit within 7 days after the administration of the 
study drug. A month is defined as 4 weeks for the purpose of this protocol.
4.2. Study Schematic
Figure 1
Study Schematic
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4.3. Schedule of Assessments
Table 1
Schedule of Assessments
Procedure
Screening 
Visit
(3-28 days)1
Baseline Visit 
(Randomization)1
Treatment Phase
End of 
Treatment 
Visit (within 7 
days of 
treatment)15
Onset of 
moderate or 
severe 
migraine2
15, 30, 45, 
60 and 90 
minutes 
Post-Dose
2, 3, 4, 6, 8 
hours Post-
Dose
24 hours 
Post-Dose
48 hours 
Post- Dose
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Prophylactic Migraine 
Medication/ 
Concomitant 
Medication3
X
X
X
Assessment of 
Migraine History 
(Signs and symptoms) 
paper source4
X
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Procedure
Screening 
Visit
(3-28 days)1
Baseline Visit 
(Randomization)1
Treatment Phase
End of 
Treatment 
Visit (within 7 
days of 
treatment)15
Onset of 
moderate or 
severe 
migraine2
15, 30, 45, 
60 and 90 
minutes 
Post-Dose
2, 3, 4, 6, 8 
hours Post-
Dose
24 hours 
Post-Dose
48 hours 
Post- Dose
Safety Assessments
Physical Examination
X
X
Vital Signs/ Physical 
Measurements5
X
X
X
Clinical Safety 
Laboratory Testing
X6
X
Urine drug screen for 
drugs of abuse
X
X
ECG
X
X
Pregnancy Test7
X (serum)
X (urine)
X (urine)
X (serum)
Adverse Event and 
Serious Adverse Event 
Assessment8
X
X
X
X
X
X
X
X
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS)9
X
X
X
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Procedure
Screening 
Visit
(3-28 days)1
Baseline Visit 
(Randomization)1
Treatment Phase
End of 
Treatment 
Visit (within 7 
days of 
treatment)15
Onset of 
moderate or 
severe 
migraine2
15, 30, 45, 
60 and 90 
minutes 
Post-Dose
2, 3, 4, 6, 8 
hours Post-
Dose
24 hours 
Post-Dose
48 hours 
Post- Dose
Clinical Drug Supplies/Study Supplies
Randomization10
X
eDiary provided
X
Dispense Study Drug
X
Administer 1 dose of 
study medication11
X
Return unused study 
drug 
X
eDiary 
returned/reviewed for 
completeness12
X
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Procedure
Screening 
Visit
(3-28 days)1
Baseline Visit 
(Randomization)1
Treatment Phase
End of 
Treatment 
Visit (within 7 
days of 
treatment)15
Onset of 
moderate or 
severe 
migraine2
15, 30, 45, 
60 and 90 
minutes 
Post-Dose
2, 3, 4, 6, 8 
hours Post-
Dose
24 hours 
Post-Dose
48 hours 
Post- Dose
Efficacy Assessments13
Assessment of 
migraine pain14
X
X
X
X
X
Assessment of 
Migraine Symptoms 
(photophobia, 
phonophobia, and 
nausea – eDiary)14
X
X
X
X
X
Functional Disability 
Scale14
X
X
X
X
X
1
Screening Phase will be 3 – 28 days. The Baseline Visit may be scheduled but should only occur after all screening procedures are complete, subject meets 
inclusion/exclusion criteria, and lab test results have been received by the site. If the subject does not meet all eligibility requirements, the subject should be screen failed in the 
IWRS.
2
Subjects will use the eDiary before taking study drug to answer questions about their migraine symptoms upon experiencing a moderate or severe migraine headache. The 
subject will administer pre-dispensed study drug or matching placebo if the following criteria are met: 1) the headache remains moderate or severe; 2) the subject has 
completed all required migraine assessment questions in the eDiary, including their current most bothersome migraine symptom, and 3) the subject has not already taken 
prohibited medications (see protocol Section 5.4).
3
Subjects should keep track of their concomitant medications on the approved paper diary throughout the study. A concomitant medication paper diary will be provided to 
subjects at the Screening visit. These paper diaries should be returned to the investigational site at the End of Treatment Visit for review and electronic data capture 
(EDC) entry. Any medication taken for recurrent headache should be documented. Subjects should keep track of their rescue medications on the approved study paper 
diary provided throughout the study. A rescue medication paper diary will be provided to subjects at the Baseline visit (reference rescue medication Section 5.5 additional 
information). These paper diaries should be returned to the investigational site at the End of Treatment Visit for review and EDC entry. The paper diaries should be kept 
as source documents.
4
Migraine History, history of triptan use and CV risk factors will be recorded on paper source documents and entered into the EDC. Subjects will also be asked about their 
typical most bothersome symptom when having a migraine. 
5
Height will only be captured at the Screening Visit. Weight, body temperature, respiratory rate, blood pressure and heart rate will be collected at all time points where 
indicated. Sitting arterial systolic and diastolic blood pressure and radial artery pulse rate will be measured.
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6
All screening visit laboratory test results must be received prior to Baseline (randomization) Visit. Refer to Section 6.2.4
7
For WOCBP: A serum pregnancy test will be collected at the Screening and EOT Visit as part of the standard laboratory tests. Confirmatory urine pregnancy test for 
WOCBP will be completed on site at the Baseline Visit and any subsequent visits for confirmation at the Investigator’s discretion. Home pregnancy test will be provided 
to WOCBP after completion of Baseline Visit. WOCBP subjects must complete the urine pregnancy test at home prior to taking study drug.
8
AE and SAEs must be reported from the time of informed consent. All ongoing non-serious AEs and SAEs will be followed to resolution or until investigator deems there 
will be no further status change. SAEs that occur during the treatment period should be reported to site according to local regulatory requirements. Non-serious AEs that 
occur during the treatment period should be reported to the site at the EOT. 
9
The C-SSRS will be clinician administered on site with a paper form.
10 Subjects will be randomized in the IWRS system at the Baseline Visit (Randomization Day 01).
11 Subjects should be instructed that the dose should be taken once the migraine attack reaches moderate or severe pain and after the subject has completed all required 
migraine assessments in the eDiary. The eDiary will prompt the subject when they should take study drug. 
12 Site staff to review and confirm entries with subjects and confirm all data points are transferred to the system and reset eDiary for future subject use, PRIOR to the subject 
leaving the clinic.
13 ± Windows for timeframe around efficacy assessments (15, 30, 45, 60, 90 min, 2, 3, 4, 6, 8, 24 and 48 hours) will be automated and captured in the eDiary.
14 These scales will be captured in the eDiary. Subjects will also be asked about their most bothersome symptom at the time of reporting and treating a qualifying migraine.
15 Subjects should return to the site for their EOT visit within 7 (+4) days of study drug dosing.
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4.3.1. Screening Phase (3-28 days)
It is estimated that approximately 1,220 subjects will be screened to allow approximately 795 
subjects to be randomized at the Baseline visit. After obtaining informed consent, subjects 
will undergo all screening procedures as detailed in Table 1. All subjects who are screened 
into the study will be entered into the IWRS system. After all screening procedures are 
complete, subjects may return 3 to 28 days from signing informed consent to be randomized 
at the Baseline visit if they meet all eligibility criteria. Any subject who does not meet all 
eligibility criteria will be considered a Screen Failure.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
considered for re-screening in select circumstances (e.g., previously pregnant, screening 
window too long). Subjects who were considered screen failures may also be considered for 
re-screening provided the ineligibility was due to one of the eligibility criteria that may have 
changed due to medical intervention or one of the eligibility criteria modified in a protocol 
amendment. Adequate documentation in source records must support the previously failed 
criteria. 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.
4.3.2. Randomization Visit/Treatment Phase (Up to 45 days)
Subjects who meet all eligibility criteria will be randomized at the Baseline Visit via the 
IWRS. The subjects will be provided with an eDiary. The study personnel will instruct the 
subject on the proper use of the eDiary and ensure proper understanding and use of the tool, 
prior to the subject leaving the site.
After randomization via the IWRS, subjects will be dispensed the double-blind study drug to 
take home for up to 45 days. This study drug is to be taken when a migraine attack reaches 
moderate or severe intensity on the numeric rating scale (NRS) as indicated in the eDiary. 
Subjects will be instructed to take their study drug, as an outpatient, when (if) they have a 
migraine headache which reaches moderate or severe intensity after they answer eDiary 
questions about their current pain and symptoms and identify their currently most 
bothersome, migraine associated, symptom (phonophobia, photophobia or nausea). The 
subject will complete an eDiary for 48 hours after taking study drug to record efficacy and 
other quality of life measures. 
Subjects in this study may be randomized only once. Under no circumstances may a subject 
be re-randomized.
4.3.2.1. eDiary Data Collections
Subjects will record efficacy in their eDiary. A subject should not take study drug until the 
headache reaches moderate or severe intensity. Headache severity will be recorded using a 
4-point numeric rating scale (no pain, mild pain, moderate pain, severe pain) at the onset of 
the migraine and after dosing at time points of 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 8, 
24 and 48 hours. The presence or absence of associated symptoms (nausea, photophobia, 
phonophobia) and ratings of functional disability (4-point scale: normal, mildly impaired, 
severely impaired, requires bedrest) will be recorded at the same time points as the headache 
severity ratings. Subjects will also identify their currently most bothersome symptom before 
taking study drug. Subjects will record the date and time study therapy was taken in their 
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eDiary. Subjects who have headache pain reduced to a mild intensity or pain free intensity 
level will be considered to have achieved pain relief. 
After taking study drug, all other headache medication is prohibited during the 2 hours post 
dose. However, a subject who does not experience relief of their migraine headache at the 
end of 2 hours after dosing with study drug (and after the 2-hour assessments have been 
completed on the eDiary) will be permitted to use the following rescue medication: aspirin, 
ibuprofen, acetaminophen up to 2000 mg/day, naproxen (or any other type of nonsteroidal 
anti-inflammatory drug (NSAID)), antiemetics (e.g., metoclopramide), or baclofen. These are 
the only medications allowed for rescue treatment after 2 hours post dose of study drug. 
However, if needed, after 48-hours of taking the single dose of study drug (and before 
returning for the End of Treatment Visit) subject may take their prescribed standard of care 
medications for treatment of migraine, including triptans if not contraindicated, provided all 
of the assessments have been completed on the eDiary. Exclusionary rescue medication 
such as, opioids, ergotamines, butalbital compounds, and muscle relaxants (except baclofen 
as a rescue medication, see above) are not allowed on this study. Similarly, if the migraine is 
relieved by study drug at 2 hours after dosing but then recurs to a moderate or severe 
intensity level between 2 and 48 hours, the subject will be permitted to take the same rescue 
medication as outlined above. 
Subjects should be encouraged to treat the first qualifying (moderate to severe) migraine that 
occurs during the treatment phase. If subjects are unable to treat their first qualifying 
migraine due to scheduling, etc. the same medication restrictions would still apply (i.e. 
aspirin, ibuprofen, naproxen (or any other type of nonsteroidal anti-inflammatory drug 
(NSAID)), antiemetics (e.g., metoclopramide) or baclofen. 
Similarly, for treatment of non-qualifying migraines (i.e. mild migraines, or other headaches) 
that occur during the treatment phase before a qualifying migraine is reported, subject will 
only be permitted to use the medications listed above. Triptans and acetaminophen (over 
2000 mg/day) are prohibited after randomization except as rescue medication as described in 
Section 5.5. In all circumstances, the subject will continue to complete the eDiary for up to 
48 hours after taking the study drug.
4.3.3. Extension Phase 
Not Applicable
4.3.4. End of Treatment
Subjects will return to the study site within 7 days of study drug dosing (+4 days) for review 
of the eDiary assessment of medication compliance and monitoring of tolerability and safety 
(including vital signs, laboratory tests, and electrocardiography). If a subject has NOT 
experienced a migraine headache of sufficient severity within 45 days after randomization, 
they still are required to complete all EOT visit procedures. All subjects must return unused 
study drug and eDiary to the study site. 
4.4. Post Study Access to Therapy 
At the end of the study the sponsor will not continue to supply study drug to 
subjects/investigators. The investigator should ensure that the subject receives the 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 1,220 subjects will be screened to randomize approximately 795 subjects (265 
per arm). Subjects will be randomized in a 1:1:1 ratio to the rimegepant 25 mg, rimegepant 
75 mg, or placebo treatment groups. 
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 site’s institutional review board (IRB) or ethics committee
(EC), 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.
Migraine attacks present for more than 1 year with the age of onset of migraines prior 
to 50 years of age.
b. Migraine attacks, on average, lasting 4 – 72 hours if untreated.
c.
Not more than 8 attacks of moderate to severe intensity per month within the last 3 
months (month is defined as 4 weeks for the purpose of this protocol).
d. Subjects must be able to distinguish migraine attacks from tension/cluster headaches.
e.
Consistent migraine headaches of at least 2 migraine attacks of moderate to severe 
intensity in each of the 3 months prior to Screening Visit and maintains this 
requirement during the Screening Period.
f.
Less than 15 days with headache (migraine or non-migraine) per month in each of the 
3 months prior to the Screening visit and maintains this requirement during the 
Screening Period.
g. Subjects on prophylactic migraine medication are permitted to remain on therapy if 
the dose has been stable for at least 3 months prior to the Screening Visit, and if the 
dose is not expected to change during the course of the study. Valproic acid/valproate 
is permitted if subject is on therapy for at least 6 months 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
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a.
Subjects ≥ 18 years 
b. Women of childbearing potential (WOCBP) with male partners and men with women 
partners of childbearing potential must be using 2 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 the Screening 
Visit.
c.
At the Baseline Visit, prior to dispensing Investigational Study Drug, WOCBP must 
have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG).
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. 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.
(Deleted in a protocol amendment) 
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 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 at least 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. 
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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, 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.
Patient 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 AE or interfere with assessments of safety or efficacy 
during the course of the study. 
k. History of alcohol abuse and/or illicit drug use meeting DSM-V criteria for substance 
use disorder within 6 months of screening. Note, non-dependent use of 
cannabis/marijuana is permitted. 
l.
(Deleted in a protocol amendment)
m. (Deleted in a protocol amendment)
n. Body mass index 35 kg/m2
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.
Females of childbearing potential who are unwilling or unable to use an acceptable 
contraceptive method or abstinence to avoid pregnancy for the entire study period and 
for 60 days after the study.
b. Women with a positive pregnancy test on enrollment or prior to study drug 
administration.
5. Electrocardiogram (ECG) and Laboratory Test Findings
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a.
Estimated glomerular filtration rate (eGFR) ≤ 30 ml/min/1.73m2
b. Corrected QT interval > 470 msec (QTc by method of Fridericia), at Screening
c.
Left Bundle Branch block (LBBB)
d. (Deleted in a protocol amendment)
e.
(Deleted in a protocol amendment)
f.
Total bilirubin (T bili) > 1.5 × ULN (may be repeated once for confirmation during 
the screening period; direct bilirubin >1.5 × ULN is exclusionary for Gilbert’s 
syndrome)
g. AST or ALT > 2.0 × ULN (may be repeated once for confirmation during screening 
period)
h. Neutrophil count ≤ 1000/μL (or equivalent)
i.
HbA1c 7.5% 
j.
Other abnormal ECG that in the investigator’s opinion makes the subject unsuitable 
for a clinical trial
6. Prohibited Medications
a.
Subjects taking a prohibited medication (Refer to the Section 5.4)
7. Other Exclusion Criteria
a.
Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infection disease) illness
b. Exposure to non-biological investigational agents or investigation interventional 
treatments within the 30 days prior to Screening visit. 
c.
Exposure to biological investigational agents within the 90 days prior to Screening 
visit. 
d. Subjects who have previously participated in any study of rimegepant. 
e.
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.)
f.
Participation in any other investigational clinical trial while participating in this 
clinical trial.
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g. Subjects must complete the Baseline/ Randomization visit within 3 to 28 days of the 
Screening visit. 
h. 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.
5.4. Prohibited and Restricted Concomitant Medications
The below medications are prohibited prior to randomization and during the course of this 
study or as specified. 
1. Traditional Chinese Medicines should not be taken 14 days prior to randomization and 
throughout the study.
2. St. John’s Wort should not be taken 14 days prior to randomization 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 randomization and 
throughout the study.
6. History of use of ergotamine medications on greater than/equal 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) for at least 2 days prior to randomization.
8. History of systemic non-narcotic analgesic intake on ≥ 15 days per month for > 3 month 
(e.g. acetaminophen, NSAIDs, gabapentin etc.) for other pain indications. (Please refer to 
Section 5.5 for rescue medication).
9. Use of acetaminophen or acetaminophen containing products must be discontinued at 
least 2 days prior to randomization (acetaminophen up to 2000 mg/day is allowed as 
rescue medication, see Section 5.5 ). During the screening phase (3-28 days) use of 
acetaminophen or acetaminophen containing products at daily dosing levels of greater 
than 2000 mg/day is prohibited. 
10. The use of CGRP antagonist biologics [e.g. galcanezumab, erenumab, fremanezumab, 
eptinezumab-jjmr] is prohibited during the study. CGRP antagonist biologics must be 
discontinued 6 months prior to screening and are prohibited throughout the study. 
11. 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. 
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12. Lasmiditan (Reyvow®) is prohibited 14 days prior to randomization and throughout the 
study.
13. Marijuana and all forms of ingested or inhaled cannabidiol and THC-containing products 
usage meeting DSM-V criteria for substance use disorder.
14. Muscle relaxants (baclofen is allowed as rescue medication, see Section 5.5).
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, 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 a moderate to strong CYP3A4 inhibitor. Please see Section  
16.1.
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, dosing with 
rimegepant should be stopped and should not start again until 14 days after the last dose 
of a moderate to strong CYP3A4 inducer. Please see Section 16.1.
17. Concomitant use of strong inhibitors of the P-gp transporter with rimegepant is prohibited 
during the study. See Section 16.1.
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. Subjects on prophylactic migraine medication are permitted to remain on therapy 
provided they have been on a stable dose for at least 3 months prior to study entry. 
20. Concomitant use of LAMICTAL® (lamotrigine) is prohibited during the study.
21. Use of CefalyTM or any other device for migraine treatment is prohibited within 12 weeks 
of the Screening Visit and during the study. 
22. Low dose aspirin (e.g. up to 100 mg daily) for documented cardiovascular prophylaxis is 
allowed.
5.5. Rescue Medications
After dosing with study drug, all headache medication is prohibited during the 2 hours post 
dose. However, a subject who does not experience relief of their migraine headache at the 
end of 2 hours after dosing with study drug (and after the 2-hour assessments have been 
completed on the eDiary), will be permitted to use ONLY the following rescue medication: 
aspirin, ibuprofen, acetaminophen up to 2000 mg/day, naproxen (or any other type of non-
steroidal anti-inflammatory drug (NSAID)), antiemetics (e.g., metoclopramide), or 
baclofen. These are the only medications allowed for rescue treatment after 2 hours post 
dose of study drug.
However, if needed, after 48-hours of taking the one dose of study drug (and before coming 
in for the End of Treatment Visit) subject may take their prescribed standard of care 
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medications for treatment of migraine including triptans if not contraindicated, provided all 
of the assessments have been completed on the eDiary. Similarly, if the migraine is relieved 
by study drug at 2 hours after dosing but then recurs to a moderate or severe intensity level 
between 2 and 48 hours, the subject will be permitted to take the same rescue medication as 
above. In all circumstances, the subject will always continue to complete the eDiary entries 
through the 48-hour assessment after taking the study drug. Use of concomitant medication 
after randomization, including rescue medication, will be recorded by the subject on a paper 
diary and reported to the site. The site will record medications that were taken within 14 days 
of taking study drug (or until the End of Treatment Visit). 
During the 45 days the subject is participating in the study, if the subject has a nonqualifying 
migraine (mild migraine) or a migraine that they do not treat with study drug, the subject is 
permitted to use only the following medications: aspirin, ibuprofen, naproxen (or any other 
type of non- steroidal anti-inflammatory drug (NSAID)), antiemetics (e.g., metoclopramide), 
or baclofen.
After completing all assessments (through 48 hours and before End of Treatment Visit) in 
their eDiary, if subjects experience a migraine, they are allowed to take their standard of care 
medication (including triptans if not contraindicated and acetaminophen up to 2000 mg/day).
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. Women on hormone replacement therapy (HRT) who no longer menstruate
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 one 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 
2 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 investigational product in 
such a manner that risk of pregnancy is minimized (i.e., this study begins with signed consent 
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form through 60 days (for WOCBP) and 90 days (for men) after dosing with study drug). It is 
required that all WOCBP use 2 methods of contraception for the duration of the study. The 
2 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.
All WOCBP must administer the home pregnancy test provided at home, prior to taking 
Investigational Study Drug. If the pregnancy test is positive, subjects should not take study 
drug and should immediately contact the Study Investigator.
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 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 study materials including, but not limited to the following will be provided at the study 
start:

Investigator File/Regulatory Binder

Pharmacy Binder

Drug Accountability Logs

Paper Concomitant and Rescue Medication Logs (take home for subjects) 

Investigator Brochure

Interactive Web-based Response System (IWRS) instructions

Electronic Case Report Form (eCRF) completion instructions

eDiary: one device will be given to each randomized subject

Instructions for the eDiary and training materials for subjects 

Laboratory Kits (including home pregnancy test kit) and Laboratory Manual

Back-up forms for CT SAE report, EDP and Pregnant Partner Release of Information

Paper copies of the C-SSRS
All sites will use an EDC tool to submit study data to the CRO. Electronic Case Report 
Forms (eCRFs) will be prepared for all data collection fields including SAE Reporting. SAE 
data (including responses to queries) will be submitted to the CRO using SAE forms. 
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 CRO and Sponsor. No additional source 
documents are required for the scales and assessments (See Section 6.3) which are completed 
by the subject in the eDiary.
Safety laboratory, plasma, serum and 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. 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. 
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6.2.2. Electrocardiogram (ECG)
A standard 12-lead ECG will be recorded at the scheduled visits as outlined in Table 1. The 
investigator will determine if any ECG abnormalities are clinically significant or not. (see 
Section 16.2. Appendix 2)
6.2.3. Physical Exam 
Subjects will undergo a routine physical examination at the scheduled visits as outlined in 
Table 1. Physical examinations to include at minimum 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 and Table 1.
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. Laboratory Testing
Blood and urine samples will be obtained as outlined in Table 1 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 prior to all blood draws. 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, BUN (urea), serum 
creatinine, uric acid, ALT, AST, alkaline phosphatase, LDH, total protein, albumin, T bili, 
direct bilirubin, indirect bilirubin, CK, HbA1c. 
End of Treatment Visit:
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
Elevations in CK (>5 × 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 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.
Estimated glomerular filtration rate: eGFR will be calculated and reported by the central 
lab at each visit that clinical laboratory tests are collected as outlined in Table 1.
Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, protein, 
glucose and blood. If blood, protein or leukocytes are positive and determined clinically 
significant by the investigator, then the subject should be asked to return for an unscheduled 
visit for microscopic examination.
Urine Drug Screen: For drugs of abuse.
FSH: For WOCBP at screening, to determine WOCBP status, if required.
Additional tests may be required or obtained to evaluate laboratory abnormalities and/or AEs; 
please refer to the Laboratory Manual.
6.2.4.2. Pregnancy Testing
Pregnancy tests will be conducted (serum, urine, home pregnancy) as outlined in Table 1. All 
WOCBP should use the home pregnancy test provided at Baseline Visit. Home pregnancy 
test should be administered prior to taking Investigational Study Drug. Subjects should not 
take Investigational Study Drug if the pregnancy test is positive, and subject should 
immediately contact Study Investigator.
A serum pregnancy test will be completed at Screening and End of Treatment Visits as part 
of the standard laboratory tests (if appropriate). Confirmatory urine pregnancy test for 
WOCBP should be completed on site at Baseline Visit and any subsequent visits for 
confirmation at the Investigator’s discretion.
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.
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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
6.3.1. Pain
Subjects are given an eDiary to record their migraine pain score, on a 4-point numeric rating 
[no pain, mild pain, moderate pain, severe pain] at the time points indicated in Table 1. 
6.3.2. Nausea, Phonophobia and Photophobia
The migraine associated symptoms of photophobia, phonophobia and nausea are measured on 
a 2 point scale (present or absent), using the eDiary, at the time points listed in Table 1. If a 
subject reports the presence of a symptom, the subject is then asked to rate the severity of the 
symptom on a 4-point scale (none, mild, moderate or serve). All assessments are done using 
the eDiary.
The subjects are also asked to identify their most bothersome symptom on the eDiary 
(nausea, phonophobia or photophobia) at the onset of the migraine to be treated. The most 
bothersome symptom must be identified before the subject takes study drug. 
6.3.3. Rescue Medication
The subject’s use of rescue medication is recorded by the subject in a paper diary.
6.3.4. Functional Disability
Impact of treatment on functional disability will be assessed using a single-question scale. 
Subjects rate the level of disability they perceive as a result of their migraine in performing 
normal actions. This is done in the eDiary, at the times indicated in Table 1, using a 4-point 
numeric rating scale: Normal Function, Mild Impairment, Severe Impairment, Required 
Bedrest. 
6.4. Early Discontinuation from the Study
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)
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
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of 
the investigator or sponsor, indicates that continued participation in the study is not in the 
best interest of the subject

Pregnancy

Termination of the study by Sponsor.

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
All subjects who discontinue should comply with protocol specified End of Treatment 
procedures as outlined in Table 1. 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).
6.4.1. 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.
7. STUDY DRUG MANAGEMENT
7.1. Description of Study Drug
7.1.1. Investigational Product
An investigational product, 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
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form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form.
The investigational product should be stored in a secure area according to local 
regulations. It is the responsibility of the investigator to ensure that investigational 
product is only dispensed to study subjects. The investigational product must be 
dispensed only from official study sites by authorized personnel according to local 
regulations.
In this protocol, investigational product is/are: rimegepant and the matching placebo 
7.1.2. Packaging, Shipment and Storage
Study drug will be packaged in blister packaging, which is heat sealed into a wallet. Study 
drug is a double-blind double dummy design to maintain the blind, as the different 
rimegepant strength ODTs have different flavours. 
Responsible study personnel 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. Each subject will be assigned a unique subject number 
through the appropriate study-related system. The subject number must not be reused for any 
other study subjects. 
After completion of all screening evaluations all eligible subjects will be randomized in a 
1:1:1 ratio to the rimegepant 25 mg, 75 mg 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.
Randomization schedules will be generated and kept by the IWRS vendor in a secure network 
folder with access limited to only unblinded team members. Each subject who is qualified for 
treatment will be randomized via the IWRS randomization option. Subjects will maintain 
their subject number assigned at screening throughout the trial. The IWRS will provide the 
double-blind treatment assignments.
The randomization will trigger a blister card number for the randomized treatment type. The 
study drug will be dispensed at the time of randomization. 
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7.2.2. Selection and Timing of Dose and Administration
Two ODTs will be dispensed to each subject as shown in Table 2. There are no dose 
adjustments in this study and subjects will receive 2 ODTs to treat one migraine headache of 
moderate or severe intensity within 45 days of randomization (Baseline Visit). Subjects will 
be dispensed the study drug at randomization (Baseline Visit) and will take 2 ODTs at the 
time of moderate or severe migraine headache onset ONLY after answering questions 
regarding their migraine symptoms in the eDiary device. The 2 ODTs should be taken 
together (at the same time) 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.
Table 2
Treatment Assignment to each group
25 mg or
matching placebo
75 mg or
matching placebo
Rimegepant 25 mg group
25 mg 
Matching placebo (matches 
rimegepant 75 mg)
Rimegepant 75 mg group
Matching placebo (matches 
rimegepant 25 mg)
75 mg 
Placebo group
Matching placebo (matches 
rimegepant 25 mg) 
Matching placebo (matches 
rimegepant 75 mg) 
7.2.3. Dose Modifications
There will be no dose adjustments in this study.
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 investigational 
product is critical to the subject’s management, the blind for that subject may be broken by 
the treating physician.
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 investigational 
product 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.
7.4. Treatment Compliance
Responsible study personnel will dispense the study drug. Accountability and compliance 
verification should be documented in the subject’s study records. 
Subjects will be counseled on the importance of taking the study drug as directed when a 
migraine occurs and reaches moderate or severe intensity. If the subject does not have a 
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migraine or take their study drug within 45 days of the Baseline Visit, they should return to 
the clinic for their End of Study Visit and return their unused study drug. 
Subjects who take study drug will be asked to return all empty blister packaging and wallets 
to the study site at the End of Study Visit. 
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 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 investigational product, whether or not considered relate to the investigational 
product. 
AEs 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.
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 
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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 2 types of AEs, SAEs and Non-Serious AEs. Subjects should be instructed to notify 
the Investigator when a SAE 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
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
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, 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)
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 this study (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).
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 
informed consent form (ICF) is signed and throughout the course of the study up to and 
including the End of Treatment 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. 
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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 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, 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, 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:
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. 
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8.2.1. Collection and Reporting of Non-Serious Adverse Events
The collection of non-serious AE information should begin at the Baseline Visit through the 
End of Treatment Visit. 
Non-serious AEs 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 the 
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 
antidote(s) administered.
Asymptomatic dosing errors should be reported as deviations.
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 
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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. 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 
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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, or the female 
partner of a male study subject, is pregnant or may have been pregnant at the time of the 
investigational product exposure, including during at least 6 half-lives after the product 
administration, the investigational product will be permanently discontinued in an appropriate 
manner (i.e., dose tapering if necessary for subject’s safety).  Protocol-required procedures 
for the study discontinued and the follow-up must be performed on the subject unless 
contraindicated by the pregnancy (ie, 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 to the Pfizer DSU by either using the PSSA tool or by 
completing an EDP Supplemental Form and 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 as 
described above.
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 as described above. 
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.
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
A female nonsubject 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. 

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 
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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 nonsubject is found to be breastfeeding while being exposed or having been 
exposed to study intervention (ie, environmental exposure). An example of 
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 via 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. 
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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.
9. STATISTICS
Complete details on the statistical methods for this study may be found in the Statistical 
Analysis Plan (SAP).
9.1. Sample Size
This study will randomize a total of 795 subjects in a 1:1:1 ratio to rimegepant 25 mg, 
rimegepant 75 mg, or placebo. It is anticipated that this will result in approximately 750 
subjects in efficacy analysis set, with roughly 250 subjects in each treatment arm.
Although testing strategy is changed in Protocol version 4.0 and formal hypothesis testing 
will no longer be conducted for rimegepant 25 mg, the original sample size will remain as it 
is. The sample size for this study was designed to provide 80% power to test each of the 
2 rimegepant doses against placebo at a Bonferroni corrected 2-sided alpha level of 0.025 
using a chi-square test. The sample size estimate is based on historical data from pivotal 
study BHV3000-303, in which the rates of pain freedom were 10.9% for placebo and 21.2% 
for Rimegepant.
9.2. Analysis Set
The following analysis sets will be used for statistical analyses, as applicable:

Enrolled: Subjects who sign an ICF and are assigned a subject identification number. 

Full: Subjects in the enrolled analysis set who receive a randomization treatment 
assignment from the IWRS (rimegepant 25 mg, 75 mg or placebo).

Safety: Subjects in the enrolled analysis set who take study therapy (rimegepant 25 mg,  
rimegepant 75 mg, or placebo).

Efficacy: Subjects in the full analysis set who are randomized only once, take study 
therapy, have a migraine of moderate or severe pain intensity at the time of treatment, and 
provide at least one post-dose efficacy data point. 
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9.3. Statistical Methods
9.3.1. Demographic and Baseline Characteristics
Tabulations of demographic and baseline characteristics will be produced for the efficacy and 
safety analysis sets.
9.3.2. Primary Endpoint(s)
BHV-3000 (rimegepant) 75 mg is tested for superiority to placebo, at a 2-sided alpha level of 
0.05, on the primary endpoint of pain freedom at 2 hours post-dose. For rimegepant 25 mg, 
formal hypothesis testing will not be conducted, and the nominal p-value will be provided 
only for descriptive purposes.
The endpoint will be evaluated using Mantel-Haenszel risk estimation with stratification by 
the use of prophylactic migraine medication (yes or no) for the efficacy analysis set. The 
difference estimate (rimegepant – placebo), 95% CI, and p-value will be reported for each 
rimegepant treatment group versus placebo. Subjects with missing data at 2 hours post-dose 
will be imputed to be failure (i.e., Non-completer = Failure; NC=F). 
Subjects who use rescue medication  at or before the assessment of their primary endpoint 
will be classified as failures. Sensitivity analyses are described in the Statistical Analysis Plan 
(SAP).  
9.3.3. Secondary Endpoint(s)
The same statistics for secondary endpoints (as listed in Section 3.2) will be presented as 
those for the primary endpoint. 
For endpoints based on a single time point, such as pain freedom at 2 hours post-dose, 
subjects with missing data at a single time point will be classified as failures (NC=F). For 
endpoints based on multiple time points, such as sustained pain relief from 2 to 48 hours 
post-dose, subjects with missing data at (1) 2, 24, or 48 hours post-dose, or (2) more than 1 
time point from 3 to 8 hours post-dose will also be classified as failures.
For all secondary endpoints except the rescue medication use within 24 hours post-dose, 
subjects who use rescue medication at or before the assessment of their endpoint will be 
classified as failures.
See section 9.3.5 for safety endpoints.
9.3.4. Multiplicity Correction
For rimegepant 75 mg, if the primary endpoint test is significant, then the secondary 
endpoints will be evaluated using a hierarchical gate-keeping procedure, with each test in the 
hierarchy conducted at alpha=0.05. Testing will stop at the first non-significant endpoint. 
Nominal p-value will still be reported but will not be used for inference purpose.
These secondary endpoints will be tested in the order shown in the Study Objectives section 
of this protocol.
For rimegepant 25 mg, formal hypothesis testing will not be conducted, and the nominal p-
values will be presented only for descriptive purposes as described in Section 9.3.2.
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9.3.5. Analysis of Safety
The investigators will determine the intensity of AEs and the relationship of AEs to study 
therapy. The investigators’ terms will be coded and grouped by system organ class using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA) available. AEs 
will be presented by system organ class and preferred term. In tables by intensity, if a subject 
had 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.
Deaths will be listed for the enrolled analysis set without regard to onset.
The frequencies of the following on-treatment safety events and findings will be summarized 
by treatment group for the safety analysis set: SAEs; AEs by intensity; AEs by relationship to 
study drug; laboratory test abnormalities by toxicity grade; and liver function test elevations 
based on fold changes above the upper limit of normal.
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). If a subject 
has a laboratory test abnormality with different toxicity grades over time, then only the 
highest toxicity grade will be reported.
Further safety analyses will be described in the SAP.
9.4. Schedule of Analyses
There is a final analysis after the last subject has his/her last visit. No interim analyses are 
anticipated.
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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 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 IECs 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 subjects 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. 
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 
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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 sample ICF which will 
include all elements required by ICH, GCP and applicable regulatory requirements. The 
sample ICF 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 ICF 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 ICF versions and a copy of each version of the IRB/IEC approved protocol and ICF 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. 
The ICF 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. 
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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 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 “bona-fide 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 
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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 nonstudy 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 investigational product (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
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.
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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. 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 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 ICF 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. In case of data transfer, the sponsor will protect the confidentiality of 
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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 inhibitors is 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/DrugInter
actionsLabeling/ucm093664.htm#table3-2
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/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 – 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.

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.
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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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16.3. APPENDIX 3 – 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 4.3, Schedule of Assessments: history 
of triptan use and CV risk factors added 
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 5.2, Inclusion Criteria: inclusion 
criteria 2g modified.
Updated Section 5.3, Exclusion Criteria: exclusion 
criteria 1a, 1b, 2i, 2n, 5f, 5g and 5i modified.
Updated Section 5.4, Prohibited and Restricted 
Concomitant Medications: #8,9 and 18 modified.
Updated Section 5.5, Rescue Medications: Revision to 
upper limit of acetaminophen dose from 1000 mg/day 
to 2000 mg/day.
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.
27-Feb-2023
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17. REFERENCES
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Sakai F, Igarashi H. Prevalence of migraine in Japan: a nationwide survey. 
Cephalalgia 1997;17:15-22.
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Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new 
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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.
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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.
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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.
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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.
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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.
8.
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.
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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.
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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.
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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.
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Biohaven-NurtecODT. Nurtec ODT USPI. . 2021.
13.
Headache Classification Committee of the International Headache Society (IHS) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
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.
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SAP_001.pdf: 
 
Statistical Analysis Plan 
Confidential
Protocol BHV3000-309 (C4951021)
Page 1 of 81
Pfizer Confidential 
 
Protocol BHV3000-309 (C4951021) 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Rimegepant for Migraine Prevention in Japanese 
Subjects 
 
Statistical Analysis Plan 
 
 
Version 2 
Date: 23-Apr-2024 
 
 
 
 


Statistic al A n al ysis Pla n
C o nfi de nti al
Pr ot oc ol B H V 3 0 0 0- 3 0 9 ( C 4 9 5 1 0 2 1)
Pa g e 2 of 8 1
Pfiz er C o nfi de nti al
SI G N A T U R E P A G E
Pr ot oc ol Title: 
A P h ase 3, Ra n d o mi ze d, D o u bl e- Bli n d, Pl ace b o-
C o ntr olle d St u d y t o E val u at e t h e Efficac y a n d Safet y of 
Ri me ge p a nt f or Mi grai ne Pr e ve nti o n i n Ja pa n ese 
S u bjects
D oc u me nt V ersi o n:
2
D ate:
2 3 -A pr -2 0 2 4
A ut h or:
, Ja pa n 
Si g nat ure: _
_ _ _
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
A p p r o v al
B y si g ni n g t his d oc u m e nt, I a c k n o wle d g e t hat I ha v e rea d t h e d o c u me nt a n d a p pr o ve of t he 
pla n ne d statisti cal a nal yses des cri b e d herei n.  I a gre e t hat t h e pla n n e d statistical a nal yses are 
a p pr o priat e f or t his st u d y, are i n acc or da nc e wit h t h e st u d y o bjecti ves, a n d ar e c o nsiste nt wit h 
t he statistic al m et h o d ol o g y d es cri be d i n t he pr ot o c ol, cli ni cal d e vel o p me nt pla n, a n d all 
a p plic a ble r e g ulat or y g ui deli nes.
I ha ve disc usse d a n y q uesti o ns I ha ve re gar di n g t he c o nte nts of t his d oc u me nt wit h t he 
bi ostatistical a ut h or.
I als o u n dersta n d t h at a n y s u bs e q ue nt c ha n ges t o t he pla n ne d statisti cal a nal ys es, as descri b e d 
herei n, m a y ha v e a r e g ulat or y i m p act a n d/ or res ult i n ti meli ne a dj ust m e nts.  All c h a n ges t o t h e 
pla n ne d a n al ys es will b e des cri be d i n t he Cli ni cal St u d y Re p ort ( C S R).
 
 J a pa n 
Si g nat ure: _ _
_ _ _
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
P P D
P P D
P P D
P P D
P P D
P P D


 
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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................5 
REVISION HISTORY ..................................................................................................................6 
ABBREVIATIONS ........................................................................................................................9 
1 
BACKGROUND AND RATIONALE ................................................................................11 
1.1 
Research Hypothesis ........................................................................................................11 
1.2 
Schedule of Analyses ........................................................................................................11 
2 
STUDY DESCRIPTION ......................................................................................................11 
2.1 
Study Design .....................................................................................................................11 
2.2 
Treatment Assignment ....................................................................................................13 
2.3 
Blinding and Unblinding .................................................................................................13 
2.4 
Protocol and Protocol Amendments...............................................................................13 
3 
STUDY OBJECTIVES AND ESTIMANDS ......................................................................14 
3.1 
Objectives..........................................................................................................................14 
3.1.1 
Primary Objective ......................................................................................................14 
3.1.2 
Secondary Objectives.................................................................................................14 
3.1.3 
Exploratory Objectives ..............................................................................................15 
3.2 
Estimands..........................................................................................................................15 
3.2.1 
Primary Objective Estimand ....................................................................................17 
3.2.2 
Secondary Objective Estimands ...............................................................................18 
3.2.3 
Exploratory Objective Estimands ............................................................................20 
4 
ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS ................................23 
4.1 
Analysis Sets .....................................................................................................................23 
4.2 
Treatment Groups ...........................................................................................................24 
4.3 
Subgroups .........................................................................................................................25 
5 
SAMPLE SIZE, POWER, AND TYPE I ERROR ............................................................25 
6 
STATISTICAL ANALYSES ...............................................................................................26 
6.1 
General ..............................................................................................................................26 
6.1.1 
Programmed Output .................................................................................................26 
6.1.1.1 
Tables ....................................................................................................................26 
6.1.1.2 
Listings ..................................................................................................................27 
6.1.2 
Statistical Methods .....................................................................................................27 
6.1.3 
Handling of Missing Data ..........................................................................................27 
6.2 
Study Population ..............................................................................................................27 
6.2.1 
Analysis Sets ...............................................................................................................27 
6.2.2 
Enrollment ..................................................................................................................28 
6.2.3 
Subject Disposition.....................................................................................................28 
6.2.3.1 
Subject Disposition from Enrollment to Randomization .................................28 
6.2.3.2 
Subject Disposition from Randomization to Treatment ..................................29 
6.2.3.3 
Subject Disposition during the DBT Phase .......................................................29 
6.2.3.4 
Subject Disposition during the OLE Phase .......................................................30 
6.2.3.5 
Subject Disposition during the Follow-up Phase ..............................................30 
6.2.4 
Protocol Deviations ....................................................................................................31 


 
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6.2.4.1 
Relevant Protocol Deviations ..............................................................................31 
6.2.4.2 
Significant Protocol Deviations...........................................................................31 
6.2.5 
Baseline Characteristics ............................................................................................31 
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics ..........................32 
6.2.5.2 
Baseline Disease Characteristics.........................................................................32 
6.2.5.3 
Medical History ....................................................................................................33 
6.2.5.4 
Non-study Prior Medications ..............................................................................33 
6.2.6 
Exposure .....................................................................................................................33 
6.2.6.1 
Study Medication .................................................................................................34 
6.2.6.2 
Measurements of Treatment Compliance .........................................................36 
6.2.6.3 
Non-study Concomitant Medications .................................................................39 
6.3 
Efficacy..............................................................................................................................40 
6.3.1 
Reduction in Migraine Days per Month ..................................................................40 
6.3.1.1 
Reduction in Migraine Days per Month in the DBT Phase: Primary 
Efficacy Endpoint.................................................................................................41 
6.3.1.2 
Reduction in Migraine Days per Month in the OLE Phase.............................45 
6.3.2 
Secondary Efficacy Endpoints ..................................................................................47 
6.3.2.1 
Percentages of Subjects with Reduction in Number of Migraine Days 
per Month .............................................................................................................47 
6.3.2.2 
Acute Migraine-specific Medication Days per Month ......................................48 
6.3.2.3 
Overall Summary of Primary and Secondary Endpoints in 
Hierarchical Testing ............................................................................................50 
6.3.3 
Exploratory Efficacy Endpoints ...............................................................................51 
6.3.3.1 
Reduction in Number of Headache Days per Month in the DBT Phase.........51 
6.3.3.2 
Percentages of Subjects with Reduction in Number of Headache Days 
per Month in the DBT Phase ..............................................................................52 
6.3.3.3 
Reduction in the Number of Migraine Days per Week and Headache 
Days per Week in the First Month of the DBT Phase ......................................53 
6.3.3.4 
Acute Migraine Medication days per Month ....................................................54 
6.3.3.5 
Medication Days per Month on Planned OL Rimegepant Dosing Days.........55 
6.4 
Safety .................................................................................................................................56 
6.4.1 
Adverse Events ...........................................................................................................57 
6.4.1.1 
Deaths ....................................................................................................................57 
6.4.1.2 
AE Overviews .......................................................................................................58 
6.4.1.3 
On-DBT AEs.........................................................................................................58 
6.4.1.4 
On-OL Rimegepant AEs .....................................................................................59 
6.4.1.5 
On-DB or OL Rimegepant AEs ..........................................................................59 
6.4.1.6 
Follow-up AEs ......................................................................................................59 
6.4.2 
Laboratory Tests ........................................................................................................60 
6.4.2.1 
Laboratory Test Worst Abnormalities ..............................................................60 
6.4.2.2 
LFT Elevations .....................................................................................................61 
6.4.2.3 
Laboratory Test Changes from Baseline over Time .........................................62 
6.4.3 
Vital Signs and Physical Measurement ....................................................................62 
6.4.3.1 
Vital Sign and Physical Measurement Changes from Baseline over 
Time .......................................................................................................................63 
6.4.3.2 
Vital Sign and Physical Measurement Abnormalities ......................................63 


 
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6.4.4 
Electrocardiograms....................................................................................................63 
6.4.4.1 
ECG Changes from Baseline over Time ............................................................63 
6.4.4.2 
ECG Abnormalities .............................................................................................64 
6.4.5 
C-SSRS ........................................................................................................................64 
6.4.6 
Safety Narrative Subject Identifiers.........................................................................64 
6.5 
Outcomes Research ..........................................................................................................65 
6.5.1 
MSQoL ........................................................................................................................65 
6.5.2 
MIDAS ........................................................................................................................66 
6.5.3 
EQ-5D-5L....................................................................................................................67 
7 
CONVENTIONS ...................................................................................................................68 
7.1 
Derived Dates ...................................................................................................................68 
7.2 
Analysis Periods ...............................................................................................................70 
7.3 
Analysis Visit Windows ...................................................................................................71 
8 
CONTENT OF REPORTS ..................................................................................................72 
8.1 
PCD Final CSR ................................................................................................................72 
8.2 
Week 24 Final CSR ..........................................................................................................73 
8.3 
LSLV Final CSR ..............................................................................................................73 
9 
APPENDICES .......................................................................................................................73 
9.1 
Relevant Protocol Deviations ..........................................................................................73 
9.2 
eDiary Efficacy .................................................................................................................77 
9.2.1 
Efficacy Parameters ...................................................................................................77 
9.2.2 
eDiary Efficacy Data Day ..........................................................................................77 
9.2.3 
Acute Migraine Medication Day...............................................................................78 
9.2.4 
Acute Migraine-specific Medication Day.................................................................78 
9.2.5 
Migraine Day ..............................................................................................................78 
9.2.6 
Headache Day .............................................................................................................79 
9.3 
SAS Code ..........................................................................................................................79 
9.3.1 
Linear Mixed Effects Model with Repeated Measures ..........................................79 
9.3.2 
Linear Regression Model ..........................................................................................80 
9.4 
Study Drug Dosing Day ...................................................................................................80 
10 REFERENCES .....................................................................................................................81 
 
LIST OF TABLES 
Table 1 
Primary Objective Estimand ..............................................................................17 
Table 2  
Secondary Objective Estimands .........................................................................18 
Table 3  
Exploratory Objective Estimands ......................................................................21 
Table 4 
Treatment Group Presentation in Tables by Analysis Set ...............................26 
Table 5 
Analysis Visit Windows .......................................................................................71 
  
LIST OF FIGURES 
Figure 1  
Study Schematic ...................................................................................................13 


 
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REVISION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Section 6.3.1.1: Changed the analysis set for the frequency table of missing efficacy 
data in the OP and DBT phase. SE estimation method in the linear mixed effects model 
for the main analysis was changed to use Huber-
. 
Added subgroup analyses by chronic migraine according to ICHD 3rd edition. For the 
J2R macros, edited the description on the Ndraw and thin parameters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase
ASE 
Asymptotic standard error 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CGRP 
Calcitonin gene-related peptide 
CI 
Confidence interval 
CRF 
Case report form 
CSR 
Clinical study report 
DB 
Double-blind 
DBT 
Double-blind treatment
eDiary 
Electronic diary 
eDISH 
Evaluation of drug-induced serious hepatotoxicity
eGFR 
Estimated glomerular filtration rate 
EOD 
Every other day 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
FCS 
Fully conditional specification 
GLM 
Generalized linear model 
GLMEM 
Generalized linear mixed effect model 
IP 
Investigational product 
IWRS 
Interactive web response system 
LFT 
Liver function test 
LSM 
Least-squares mean 
MDRD 
Modification of diet in renal disease 
MSQoL 
Migraine Specific Quality of Life  
ODT 
Orally disintegrating tablet 
OL 
Open-label 
OLE 
Open-label extension 
PCD 
Primary completion date 
P-gp 
Permeability glycoprotein 
PRN 
Pro re nata


 
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PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SE 
Standard error
SI 
Systeme Internationale 
SOC 
System organ class 
TBL 
Total bilirubin 
TLF 
Table listing figure 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 


 
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1 BACKGROUND AND RATIONALE 
This document presents the statistical analysis plan (SAP) for Protocol  C4951021: A Phase 3 
Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Rimegepant for Migraine Prevention in Japanese Subjects. 
This SAP contains the analysis details and methodology to answer the study objectives, 
including planned tables, listings, and figures (TLFs), which provide the basis for the results 
section of the clinical study report (CSR). 
This SAP also references the Rimegepant/Zavegepant Core SAP, which is hereafter referred to 
 
1.1
Research Hypothesis   
 
1.2
Schedule of Analyses 
There are 3 planned database locks: (1) primary completion date (PCD) database lock for the 
PCD final CSR, which will occur after the last subject completes the Week 12 Visit; (2) Week 24 
database lock for the Week 24 final 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 final CSR, which will occur after the last subject completes the
Follow-up Week 2 Visit.  
No interim analyses are planned. 
2 STUDY DESCRIPTION
2.1
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy 
and safety of rimegepant in migraine prevention in Japanese subjects.  
 
  
Observation Phase (OP): Lasts approximately 28 days. Includes the Screening Visit and Pre-
randomization Evaluation Visit which must occur within 4 days of the Baseline Visit  
Double-blind Treatment (DBT) Phase:   
Lasts up to 12 weeks, and includes the Baseline Visit, and Week 2, 4, 8, and 12/End of 
Treatment (EOT) Visits  
Subjects are randomized 1:1 to one of the following 2 treatment groups at the Baseline 
Visit: 
Rimegepant 75 mg dosed every other day (EOD)  


 
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Placebo matching rimegepant 75 mg dosed EOD.  
o
  
o
 
o
  
   
o
   
o
  
o
 
o
 
  
o
 
o
  
 
 


 
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Figure 1  
Study Schematic 
 
2.2
Treatment Assignment 
The Interactive Web Response System (IWRS) assigns a subject identifier number at the 
Screening Visit. 
The IWRS randomizes eligible subjects to treatment groups (see Section 2.1) at the Baseline 
Visit. Randomization is stratified by prior prophylactic migraine medication use (yes or no).  
The IWRS also assigns specific container numbers for study drug to be dispensed at the Baseline 
Visit and subsequent visits in the DBT and OLE Phases. 
2.3
Blinding and Unblinding 
This study is blinded through the PCD database lock (see Section 1.2). Draft TLFs produced for 
the PCD final CSR are produced with dummy treatment groups prior to the PCD database lock. 
Otherwise, TLFs for the PCD final CSR, Week 24 final CSR, and LSLV final CSR are produced 
unblinded. 
2.4
Protocol and Protocol Amendments 
C4951021 SAP Version 1 is based on C4951021 Protocol Version 4 (27-Feb-2023). 
C4951021 SAP Version 2 is based on C4951021 Protocol Version 5 (04-Aug-2023). Protocol 
changes that affected statistical analyses were the following: changing the sponsorship to Pfizer; 
stating that there are 3 planned database locks and 3 final CSRs; using robust standard error (SE) 
estimation methods; excluding subject as a random effect from linear mixed effects models; and 
replacing Cochran-Mantel-Haenszel test with Mantel-Haenszel risk estimation. 


 
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3 STUDY OBJECTIVES AND ESTIMANDS 
3.1
Objectives 
A month is defined as 4 weeks (28 days) for the purpose of this protocol. 
3.1.1 
Primary Objective 
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 DBT Phase.   
3.1.2 
Secondary Objectives 
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 DBT 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 DBT 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 DBT 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 
DBT Phase. 
5. To compare the 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 DBT Phase 
between rimegepant and placebo. 
6. To compare the change from baseline in the Migraine Disability Assessment (MIDAS) total 
score at Week 12 of the DBT Phase between rimegepant and placebo. 
7. To compare the change from baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
visual analog scale (VAS) score at Week 12 of the DBT 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 DBT and OLE Phases. 
9. To evaluate the frequency of ALT or AST > 3x ULN concurrent with total bilirubin > 2x 
ULN in subjects treated with rimegepant during the DBT and OLE 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 DBT and OLE Phases. 
3.1.3 
Exploratory Objectives 
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 DBT 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 DBT 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 DBT 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 OLE 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 OLE 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 DBT 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 OLE 
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 DBT and OLE Phases. 
3.2
Estimands 
An estimand is the target of estimation to address the scientific question of interest posed by a 
study objective. The 4 attributes of an estimand include the population of interest, endpoint of 
interest, summary of the endpoint, and specification of how intercurrent events are reflected in 
the scientific question of interest.
For all objectives, the population of interest is defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population for approval. Refer to the protocol for 
inclusion/exclusion criteria. 


 
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Intercurrent Events 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the endpoint or affect its interpretation.  
Study drug discontinuation before the time point of interest defining the endpoint is considered 
an intercurrent event.  
For efficacy objectives assessed with a continuous endpoint during the DBT Phase, study 
is that had subjects not discontinued DB study drug, their efficacy would have been similar to 
the efficacy of subjects from the same treatment group and randomization stratum who did 
not discontinue DB study drug. All observed values of the endpoint of interest are excluded 
after DB study drug discontinuation plus 1 day (see Section 7.2), and statistical methods are 
used to estimate the treatment effect that would have been seen had the intercurrent event not 
occurred.  
For efficacy objectives assessed with a binary endpoint during the DBT Phase, DB study 
intercurrent event is integrated as a component of the endpoint. All observed values of the 
endpoint of interest are excluded after DB study drug discontinuation plus 1 day (see Section 
7.2), and subjects with missing data are considered failures. 
For efficacy objectives assessed during the OLE Phase, OL study drug discontinuation is 
-on-
occurrence of the intercurrent event of interest. All observed values of the endpoint of 
interest are used on or before OL study drug discontinuation + 1 day (see Section 7.2). 
-on-treatment 
strategy . All observed values of the endpoint of interest are used on or before study drug 
discontinuation + 7 days (see Section 7.2 and the Core SAP).  
. All observed 
values of the endpoint of interest are used regardless of study drug discontinuation. 
Non-study prophylactic migraine medication use before the time point of interest defining the 
endpoint is considered an intercurrent event. For all objectives, this intercurrent event is handled 
with a treatment policy strategy; all observed values of the endpoint of interest are used.  
Nonstudy acute migraine-specific medication use before the time point of interest defining the 
endpoint is also considered an intercurrent event, except for efficacy objectives based on acute 
migraine-specific medication days or acute migraine medication days.  
For efficacy objectives based on migraine days or headache days, this intercurrent event is 
handled with a composite strategy, such that acute migraine-specific medication use is part of 
the endpoint definition of migraine days and headache days.  
For safety and outcomes research objectives, this intercurrent event is handled with a 
treatment policy strategy, such that all observed values of the endpoint of interest are used. 


 
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Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura before the 
time point of interest defining the endpoint is also considered an intercurrent event, except for 
the efficacy objective based on acute migraine medication days.  
For efficacy objectives based on headache days, this intercurrent event is handled with a 
composite strategy, such that medication use is part of the endpoint definition of headache 
days.  
For all other efficacy, safety, and outcomes research objectives, this intercurrent event is 
handled with a treatment policy strategy, such that all observed values of the endpoint of 
interest are used. 
See Section 4.1 for analysis sets that are used to assess endpoints. 
 
 
Migraine days, acute migraine-specific medication days, acute migraine medication days, 
headache days, MSQoL domain scores, MIDAS scores, and EQ-5D-5L VAS score are derived 
from eDiary data from the external source YPrime. Acute migraine-specific medications are 
triptans and ergotamine. Acute migraine medications are triptans, ergotamine, and other 
protocol-allowed medications to treat headache (migraine or nonmigraine) or aura taken on 
migraine days. 
AEs are determined from AE CRFs.  
Grade 3 to 4 laboratory test abnormalities are determined from laboratory test values graded 
using standardized criteria. Laboratory test results are from an external central laboratory and 
local laboratory test CRFs.  
3.2.1 
Primary Objective Estimand 
The estimand corresponding to the primary endpoint is shown in Table 1. 
Table 1 
Primary Objective Estimand 
  
 
  
  
  
  
  
  
 
 


 
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3.2.2 
Secondary Objective Estimands
 
Table 2  
Secondary Objective Estimands  
  
 
  
 
  
  
  
  
 
 
 
  
 
  
  
  
 
  
  
 
 
 
 
  
  
 
  
 
  
  
 
 
 
  
  


 
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3.2.3 
Exploratory Objective Estimands 
The estimands corresponding to the exploratory objectives are shown in Table 3.


 
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Table 3  
Exploratory Objective Estimands 
Objective 1 
Mean reduction from baseline in the number of migraine days per month by 
intensity (total; moderate or severe) in each month and over the entire course of 
the DBT Phase 
Efficacy Endpoint 
Changes from the OP in the number of migraine days per month in each month and 
over the entire DBT Phase by pain intensity (total; moderate or severe) 
Summary 
Changes from the OP by treatment group using descriptive statistics and linear mixed 
effects model with repeated measures, and difference between treatment groups from 
the model for the DBT migraine analysis set 
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
 
 
 
Objective 2 
Proportions 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 over the entire course of 
the DBT Phase 
Efficacy Endpoint 
Proportions of subjects with  50% reduction, 75% reduction, and 100% reduction 
from the OP in the number of migraine days per month in each month and over the 
entire DBT Phase by pain intensity (total; moderate or severe) 
Summary 
Percentages by treatment group, and difference in percentages between treatment 
groups using Mantel-Haenszel risk estimation for the DBT migraine analysis set 
Intercurrent Events 
Study drug discontinuation: composite strategy 
 
 
 
Objective 3 
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 DBT 
Phase 
Efficacy Endpoint 
Changes from the OP in the number of migraine days per week during DBT in each 
week of the first 4 weeks by pain intensity (total; moderate or severe) 
Summary 
Changes from the OP by treatment group using descriptive statistics and linear mixed 
effects model with repeated measures, and difference between treatment groups from 
the model for the DBT first month migraine analysis set
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 


 
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Objective 4
Mean reduction from baseline in the number of migraine days per month by 
intensity (total; moderate or severe) in each month and over the entire course of 
the OLE Phase 
Efficacy Endpoint 
Mean changes from the OP in the number of migraine days per month in each month 
and over the entire OLE Phase by pain intensity (total; moderate or severe)  
Summary 
Changes from the OP by treatment group using descriptive statistics for the OL 
rimegepant migraine analysis set 
Intercurrent Events 
Study drug discontinuation: while-on-treatment strategy 
 
 
 
Objective 5 
Proportions 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 over the entire course of 
the OLE Phase 
Efficacy Endpoint 
Proportions of subjects with  50% reduction, 75% reduction, and 100% reduction 
from the OP in the number of migraine days per month in each month and over the 
entire OLE Phase by pain intensity (total; moderate or severe)  
Summary 
Percentages by treatment group for the OL rimegepant migraine analysis set 
Intercurrent Events 
Study drug discontinuation: while-on-treatment strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 6 
Mean number of acute migraine-specific medication days per month and acute 
migraine medication days per month in each month and over the entire course of 
the DBT Phase 
Efficacy Endpoint 
Mean number of acute migraine-specific medication days per month and acute 
migraine medication days per month in each month and over the entire DBT Phase
Summary 
Values by treatment group using descriptive statistics and linear mixed effects model 
with repeated measures, and difference between treatment groups from the model for 
the DBT migraine analysis set 
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
 
 
 
Objective 7 
Mean number of acute migraine-specific medication days per month and acute 
migraine medication days per month in each month and over the entire course of 
the OLE Phase 


 
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Efficacy Endpoint 
Mean number of acute migraine-specific medication days per month and acute 
migraine medication days per month in each month and over the entire OLE Phase 
Summary 
Values by treatment group using descriptive statistics for the OL rimegepant migraine 
analysis set
Intercurrent Events 
Study drug discontinuation: while-on-treatment strategy 
 
 
 
Objective 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 during the DBT and OLE Phases 
Outcomes Research 
Endpoint  
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 at Week 12 of the DBT Phase and Week 24 and 
Week 52 of the OLE Phase 
Summary  
DBT Phase: Change from baseline by treatment group using descriptive statistics 
and linear regression model, and difference between treatment groups from the 
model for the DBT efficacy analysis set  
OLE Phase: Change from baseline by treatment group using descriptive statistics 
for the OL rimegepant efficacy analysis set  
Intercurrent Events  
Study drug discontinuation: treatment policy strategy 
  
 
 
4 ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS 
4.1
Analysis Sets 
 
 
 
 
o


 
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o
 
 
o
 
o
 
DBT efficacy: subjects in the full analysis set who (1) are randomized only once, and (2) take 
 1 dose of DB study drug. This analysis set is used mainly to assess outcomes research 
endpoints during the DBT Phase. 
o
DBT migraine: subjects in the DBT efficacy analysis set with  14 days of eDiary data (not 
necessarily consecutive) in both the OP and  1 month (4-week interval) during the DBT 
Phase (see Section 6.3.1.1). This analysis set is used to assess migraine days, headache 
days, acute migraine-specific medication days, and acute migraine medication days during 
the DBT Phase. 
o
DBT first month migraine: subjects in the DBT 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 DBT Phase (see Section 6.3.3.1). This analysis set is used to assess 
migraine and headache days per week during the DBT Phase. 
OL rimegepant efficacy: subjects in the DBT efficacy analysis set who take  1 dose of OL 
rimegepant. This analysis set is used to assess outcomes research endpoints during the OLE 
Phase. 
o
OL rimegepant migraine: subjects in both the DBT migraine and OL rimegepant efficacy 
analysis sets with  14 days of eDiary efficacy data (not necessarily consecutive) in  1 
month (4-week interval) in the OLE Phase. This analysis set is used to assess migraine 
days, headache days, acute migraine-specific medication days, and acute migraine 
medication days during the OLE Phase. 
See Section 7.1 for derived dates and Section 7.2 for analysis periods. 
4.2
Treatment Groups 
Treatment groups in the DBT Phase are rimegepant 75 mg ODT and placebo ODT. The safety 
analysis sets are assessed by as-treated treatment group (i.e., actual treatment received), the full, 
DBT efficacy, and migraine analysis sets are assessed by as-randomized treatment group, and the 
enrolled analysis set is assessed overall.  


 
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If a subject takes  1 dose of planned randomized DB study drug, then that subject is considered 
to have as-treated treatment group equal to as-randomized treatment group (see Section 6.2.6.2).  
  
If there are non-randomized subjects who take study drug, then the as-randomized treatment 
analysis set.  
4.3
Subgroups
Subgroup tables present results by subgroup level for subjects with nonmissing subgroup level 
data, unless otherwise specified. Subgroup levels may be redefined or combined based on the 
availability of data.
The following efficacy subgroups are of interest for the DBT migraine analysis set: 
Randomization stratum: stable prophylactic migraine medication use through randomization 
(yes or no; see Section 6.2.5.4). Note that randomization strata are based on the actual data, 
not those assigned by IWRS.  Results for efficacy endpoints by randomization stratum are 
shown as described in Section 6.3. 
Historical chronic migraine according to ICHD 3rd edition (yes or no). This is from the 
Migraine History CRF. 
5 SAMPLE SIZE, POWER, AND TYPE I ERROR 
The study randomizes approximately 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 efficacy data set. Assuming rimegepant provides 
roughly a 1 day advantage over placebo on the primary endpoint, a common standard deviation 
of 3.75 days, and a 2-sided alpha level of 0.05, then the study will have roughly 80% power on 
the primary endpoint. 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.  
Type I error will be controlled by using a hierarchical gate keeping procedure. If the primary 
endpoint is significant at the 2-sided alpha level of 0.05, then secondary efficacy or outcomes 
research endpoints are tested hierarchically, each at a 2-sided alpha level of 0.05, in the order in 
which they appear in Section 3.2.2. Thus, a secondary efficacy or outcomes research endpoint is 
tested only if the preceding secondary endpoint in the hierarchy is determined to be significant 
(i.e., p-value  0.05). If a test in the hierarchy is not significant, then any further tests on 
endpoints in the sequence have p-values presented only for descriptive purposes, and no 
conclusions are drawn from those results. Note that secondary safety endpoints are not tested.  


 
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For exploratory endpoints, no attempt is made to adjust for multiplicity. Any exploratory 
endpoints for which p-values are produced are evaluated at an unadjusted, 2-sided alpha level of 
0.05 and presented only for descriptive purposes. 
6 STATISTICAL ANALYSES
 
6.1
General 
6.1.1 
Programmed Output 
A list of TLFs and corresponding templates are presented separately in a mock TLF document 
corresponding to this SAP.  
Refer to the Core SAP for additional details about programmed output.  
6.1.1.1 
Tables 
Treatment Group Presentation  
Treatment group presentation in tables by analysis set is shown in Table 4. Exceptions are 
specified in subsequent sections as needed. 
Table 4 
Treatment Group Presentation in Tables by Analysis Set 
Analysis Set 
Number of Columns 
Abbreviated Treatment Group  
Enrolled  
1 
Overall 
Full, DBT efficacy, DBT 
migraine, safety, DBT 
safety, interim safety by 
treatment group and 
{overall} 
2 to 3 
Rimegepant 
Placebo 
{Overall} 
OL rimegepant efficacy, 
OL rimegepant migraine, 
OL rimegepant safety, DB 
or OL rimegepant safety by 
treatment group/OL 
rimegepant and overall 
3 
DB Rimegepant/OL Rimegepant 
DB Placebo/OL Rimegepant 
Overall 
Follow-up safety by 
treatment group/OL 
rimegepant status and 
overall 
5 
DB Rimegepant/OL Rimegepant  
DB Placebo/OL Rimegepant  
DB Placebo to OL Rimegepant  
DB Placebo No OL Rimegepant  
Overall 
-treated DB placebo subjects in the OL rimegepant 
-treated DB placebo 


 
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subjects not in the OL rimegepant safety analysis set; note that these 2 placebo groups add to the 
/OL Rimegepant
  
Results for study population and pretreatment safety also include overall treatment group (see 
Sections 6.2 and 6.4). 
6.1.1.2 
Listings 
Unless otherwise specified, by-subject listings are sorted by randomization status (randomized, 
not randomized), site-subject ID, and additional variables such as time points, as applicable. 
Listings display as-randomized treatment group abbreviated as (1) 
 
Listings of exposure, safety parameters, and outcomes research parameters include the 
following: abbreviated name of the analysis period in which the measurement was slotted (i.e., 
PRETRT, DBT, INT, OLRMG, FU; this does not apply to exposure); analysis visit in which the 
measurement was slotted (this does not apply to exposure or AEs); measurement date/time; study 
day derived from the measurement date, and rimegepant study day  1 derived from the 
measurement date for as-randomized placebo subjects (see Section 7.3). 
Refer to the Core SAP for additional details about listings. 
6.1.2 
Statistical Methods 
Refer to the Core SAP for descriptive statistics in tables, counting rules in frequency tables, and 
rounding rules in frequency tables. 
6.1.3 
Handling of Missing Data 
All analyses are based on observed data unless otherwise specified. See Section 6.3 for statistical 
methods for handling missing data in efficacy analyses. 
6.2
Study Population 
Refer to the Core SAP for TLF contents. 
6.2.1 
Analysis Sets 
The frequency table of analysis sets described in Section 4.1 displays results by treatment group 
(as-randomized for the full and efficacy analysis sets; as-treated for the safety analysis sets), not 
randomized, and overall.   
  
The by-subject listing of analysis sets is provided for the enrolled analysis set.  
 
The administrative listing of randomization scheme and codes is provided for the full analysis 
set.  


 
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6.2.2 
Enrollment 
The frequency table of enrollment by site is provided for the enrolled analysis set, and also 
displays results for the full and safety analysis sets.  
6.2.3 
Subject Disposition 
The by-subject listing of subject discontinuation is provided for the enrolled analysis set and 
displays a separate record for each study phase (i.e., Screening, DBT, OLE and Follow-up) that 
is discontinued (i.e., completed or not completed) corresponding to each type of subject status 
CRF. The listing includes the following:  
Relevant reference dates: i.e., last contact date*, IWRS randomization date 
Study phase: Screening, DBT, OLE, or Follow-up. For each study phase: 
o
Last visit date. Derived from visit dates from the Visit Date and Unscheduled Visit 
Checklist CRFs as follows: 
Screening Phase: latest visit date before the IWRS randomization date
DBT Phase: latest visit date on or after the IWRS randomization date and through the 
on-DBT safety analysis period 
OLE Phase: latest visit date in the OL rimegepant safety analysis period 
Follow-up Phase: latest visit date in the follow-up safety analysis period 
o
Phase completion status:  
for screen failure (see Section 6.2.3.1) 
DBT, OLE, or Follow-up Phase
the reason for non-completion (see Sections 6.2.3.2, 6.2.3.4, 6.2.3.5, and 6.2.3.5) 
o
phase (OLE or Follow-
-
continuation (see Sections 6.2.3.3 and 6.2.3.4). This applies only to the DBT and OLE 
Phase. 
exists); otherwise, the maximum date collected across study population, efficacy safety, and 
7.1 for derived dates and Section 7.2 for analysis 
periods. 
6.2.3.1 
Subject Disposition from Enrollment to Randomization
The frequency table of subject disposition from enrollment to randomization is provided by 
overall for the enrolled analysis set based on the Screening Status CRF, and displays the 
following categories: 
Randomized (identified as subjects with nonmissing randomization date) 


 
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Not randomized (identified as subjects with missing randomization date)
o
Reasons for screen failure, including not reported. 
Inclusion/Exclusion Criteria CRF are also displayed as subcategories. 
6.2.3.2 
Subject Disposition from Randomization to Treatment 
The frequency table of subject disposition from randomization to treatment is provided by 
treatment group and overall for the full analysis set based on the DB Subject Status CRF, and 
displays the following categories:  
Treated with study drug (identified as subjects with nonmissing study drug start date) 
Not treated with study drug (identified as subjects with nonmissing study drug start date) 
o
Reasons for not treated (i.e., not completing the DBT Phase), including not reported.  
6.2.3.3 
Subject Disposition during the DBT Phase 
The frequency table of subject disposition during the DBT Phase is provided by treatment group 
and overall for the DBT safety analysis set based on the DB Subject Status CRF, and displays the 
following categories: 
Ongoing in the DBT Phase. These are identified as subjects with (1) missing response to the 
date. This category only exists before the PCD database lock; otherwise, subjects with 
 
date) 
study drug last date.
o
Reasons for not completing the DBT Phase, including not reported 
 Results are also shown 
by subcategories C
D
. 
o
Next phase, i.e., OLE or Follow-up 
 Subjects with missing 
response to this question after the PCD database lock are also included. Results are also 
shown by subcategories C
Did not complete the DBT 
 
o
Reasons for not continuing to the next phase, including not reported. 


 
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6.2.3.4 
Subject Disposition during the OLE Phase 
The frequency table of subject disposition during the OLE Phase is provided by treatment 
group/OL rimegepant and overall for the OL rimegepant safety analysis set based on the OL 
Subject Status CRF, and displays the following categories: 
Ongoing in the OLE Phase. These are identified as subjects with (1) missing response to the 
date. This category only exists before the LSLV database lock; otherwise, subjects with 
 
date) 
rimegepant last date. 
o
Reasons for not completing the OLE Phase, including not reported 
Continued to the Follow-
-
. 
Did not continue to the Follow-
-
. Subjects with missing 
response to this question after the LSLV database lock are also included. 
o
Reasons for not continuing to the next phase, including not reported. 
6.2.3.5 
Subject Disposition during the Follow-up Phase 
The frequency table of subject disposition during the Follow-up Phase is provided by treatment 
group/OL rimegepant status and overall for the follow-up safety analysis set based on the 
Follow-up Subject Status CRF, and displays the following categories: 
Did not formally enter the Follow-up Phase. These are identified as subjects with missing 
-
and either of the 
following: 
o
-
OLE Subject Status CRF 
o
 
A footnote explains that these are subjects with data in the follow-up safety analysis period 
who did not continue to the Follow-up Phase as per DB or OLE Subject Status CRF.
Ongoing in the Follow-up Phase. These are identified as subjects with missing response to 
-
and who are not already 
-
 


 
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This category only exists before the LSLV database lock. After the LSLV database lock, 
-
 
Completed the Follow-
-
 
Did not complete the Follow-
-
o
Reasons for not completing the Follow-up Phase, including not reported 
6.2.4 
Protocol Deviations 
6.2.4.1 
Relevant Protocol Deviations 
The frequency table of relevant protocol deviations is provided by treatment group and overall 
for the full analysis set by deviation type (eligibility, subject management), category, and 
subcategory in the order specified in Section 9.1. Results for all relevant protocol deviation 
categories and subcategories are displayed, even those with 0 counts, unless otherwise specified. 
The by-subject listing of relevant protocol deviations is provided for the full analysis set. This 
includes deviation type, category, and subcategory, which are additional sorting variables. 
6.2.4.2 
Significant Protocol Deviations 
The by-subject listing of significant protocol deviations is provided for the full analysis set, and 
is based on the protocol deviation external file provided by the data management vendor. This 
includes occurrence date, category, subcategory, and non-compliance summary, which are 
additional sorting variables. A footnote describes the raw data source and how significant 
major severity by the data management ve
 
6.2.5 
Baseline Characteristics 
Baseline characteristics include (1) demographics and other relevant baseline characteristics, (2) 
baseline disease characteristics (i.e., migraine history, and efficacy during the OP), (3) medical 
history, and (4) non-study prior medications. These are detailed in Sections 6.2.5.1 through 
6.2.5.4, respectively. 
Baseline characteristics are provided for each of the following analysis sets as follows:  
DBT migraine analysis set: Baseline characteristics (1) and (2) by treatment group and 
overall to support efficacy  
DBT safety analysis set: Baseline characteristics (1) through (4) by treatment group and 
overall to support DBT safety  
OL rimegepant safety analysis set: Demographics and other relevant OL rimegepant baseline 
characteristics by treatment group/OL rimegepant and overall to support OL rimegepant 
safety 


 
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DB or OL rimegepant safety analysis set: Demographics and other relevant DB or OL 
rimegepant baseline characteristics by treatment group/OL rimegepant and overall to support 
DB or OL rimegepant safety.  
The frequency cross table of randomization stratum (i.e., prior prophylactic migraine medication 
use [yes, no]) from IWRS and actual data (Sections 4.3 and 6.2.5.4) is provided for the full 
analysis set by treatment group and overall. 
Baseline for a parameter (e.g., weight) is defined according to analysis set; refer to the Core SAP 
for details, including handling of ties on the same measurement date (entry date/time is the 
. Note that the baseline value of a 
parameter is independent of the baseline analysis visit defined in Table 5; the latter is used only 
in by-subject listings that display visit. 
By-subject listings are provided for the enrolled analysis set for the following: demographics and 
other relevant baseline characteristics; medical history; and migraine history. Refer to the Core 
SAP for additional details.  
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics 
Refer to the Core SAP for the table of demographics and other relevant baseline characteristics, 
and calculating age at a reference date. Other relevant characteristics also include randomization 
stratum based on actual data, i.e., use of non-study stable prophylactic migraine medication 
through randomization (yes, no; see Section 6.2.5.4). Note that race and ethnicity are not 
summarized.
6.2.5.2 
Baseline Disease Characteristics 
Migraine History 
Refer to the Core SAP for the table of migraine history. The table also displays the following 
categorical variables: 
Experienced migraines for  1 year prior to screening (yes, no) 
Prophylactic migraine medications taken (yes, no). 
 
The table of efficacy endpoints per month during the OP is provided only for the DBT migraine 
analysis set, and summarizes the following efficacy parameters descriptively as continuous or 
categorical variables during the OP analysis period: 
Migraine days per month by pain intensity (total; moderate or severe). Categories are < 6,  
6, < 8,  8, < 12,  12, < 15,  15. 
Headache days per month by headache pain intensity (total; moderate or severe). Categories 
are same as for migraine days per month above.  


 
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Acute migraine-specific medication days per month. Categories are 0, > 0 to < 2,  2 to < 4, 
 4. 
Acute migraine medication days per month. Categories are the same as for acute migraine-
specific medication days per month above. 
The table of efficacy endpoints per week during the OP is provided only for the DBT first month 
migraine analysis set, and summarizes the following efficacy parameters descriptively as 
continuous or categorical variables during the OP analysis period: 
Migraine days per week by headache pain intensity (total; moderate or severe). Categories 
are < 1,  1 to < 2,  2 to < 3,  3.  
Headache days per week by headache pain intensity (total; moderate or severe). Categories 
are same as for migraine days per week above. 
See Sections 6.3.1 for migraine days per month, Section 6.3.2.2 for acute migraine-specific 
medication days per month, Section 6.3.3.3 for migraine days per week, Section 6.3.3.4 for acute 
migraine medication days per month, and Section 7.2 for the OP analysis period. 
6.2.5.3 
Medical History 
Medical history is provided by system organ class (SOC) and preferred term (PT), and displayed 
in descending order of overall frequency within SOC and PT. Refer to the Core SAP for more 
details. 
6.2.5.4 
Non-study Prior Medications 
Frequency tables of the following non-study medications are provided by therapeutic class and 
preferred name: 
Current medications: all; prophylactic migraine 
Stable prophylactic migraine medications through randomization. 
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name. See also Section 6.2.6.3.  
Stable medications through randomization are defined as those taken > 12 weeks before 
informed consent and through randomization, i.e., (1) informed consent date  imputed 
medication start date > 84 days, and (2) IWRS randomization date  imputed medication end 
date. 
Refer to the Core SAP for the definition of non-study current medication type. 
6.2.6 
Exposure 
See Section 7.1 for derived dates. 


 
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6.2.6.1 
Study Medication 
Study drug is dispensed in a wallet-type blister card with a unique wallet number. Each wallet 
has 8 tablets. During the DBT Phase, each wallet contains only rimegepant or matching placebo 
depending on the randomization. During the OLE Phase, each wallet contains only rimegepant. 
The Investigational Product (IP) Administration  DB and OL CRFs collect the dosing date, 
number of tablets taken, and dosing day type (scheduled or non-scheduled), and wallet number 
(see Section 9.4). 
The wallet type identifier associated with a wallet number is DB rimegepant, DB placebo, or OL 
rimegepant, and is obtained by merging the IP Administration CRF data with the external DB 
study drug wallet list file data and OL rimegepant wallet list file data by wallet number (i.e., kit 
number). 
The by-subject listing of study drug is provided for the safety analysis set, and presents dosing 
date, study day derived from the dosing date, number of tablets taken, dosing day type 
(scheduled, non-scheduled) wallet number, and wallet type identifier. Records with number of 
tablets taken  0 are displayed for scheduled dosing days to account for missed doses. Records 
with number of tablets taken > 0 are displayed for non-scheduled dosing days. The listing also 
displays rimegepant exposure parameters (time on DBT, time on OL rimegepant, time on DB or 
OL rimegepant, DB study drug start end dates, and OL rimegepant start and end dates), and 
identifies invalid wallet numbers. Valid DB wallet numbers are those in the DB study drug 
wallet list file. Valid OL wallet numbers are those in the OL rimegepant wallet list file. The 
listing is sorted by site-subject ID, dosing date, day type, and wallet number.  
DB Study Drug Exposure 
DB study drug exposure is summarized descriptively by treatment group, and includes the 
following parameters: 
Time on DBT (weeks), derived as (DBT end date  DBT start date + 1)/7 
Time on study drug categories: < 2,  2 to < 4,  4 to < 8,  8 to < 12,  12 weeks 
Cumulative DB exposure (tablets), derived by summing the number of tablets across records 
with complete dosing date and valid DB wallet number 
Average DB exposure (tablets per month), derived as (1) cumulative DB exposure if time on 
DB study drug < 14 days, or (2) 4 × cumulative DB exposure/time on DB study drug if time 
on DB study drug if time on DB study drug  14 days 
Total DB exposure (tablets) summed across all subjects, derived by summing cumulative DB 
exposure across all subjects 
Total DB exposure (patient-years), derived by summing (DBT end date  DBT start date + 
1)/365.25 across all subjects. 
OL Rimegepant Exposure 


 
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OL rimegepant exposure is provided descriptively by treatment group/OL rimegepant and 
overall for the OL rimegepant safety analysis set, and includes the following parameters: 
Time on OL rimegepant (weeks), derived as (OL rimegepant end date  OL rimegepant start 
date + 1)/7  
Time on OL rimegepant (weeks) categories:  12,  24, > 24  
Time on OL rimegepant milestone categories:  
o
 3 months, defined as  11 weeks 
o
 6 months, defined as  23 weeks 
Cumulative OL rimegepant exposure (tablets), derived by summing the number of tablets 
across records with complete dosing date and valid OL wallet number 
Average OL rimegepant exposure (tablets per month), derived as (1) cumulative OL 
rimegepant exposure if time on OL rimegepant < 14 days, or (2) 4 × cumulative OL 
rimegepant exposure/time on OL rimegepant if time on OL rimegepant  14 days
Total OL rimegepant exposure (tablets) summed across all subjects, derived by summing 
cumulative OL exposure across all subjects 
Total OL rimegepant exposure (patient-years), derived by summing (OL rimegepant end date 
 OL rimegepant start date + 1)/365.25 across all subjects. 
DB or OL Rimegepant Exposure 
DB or OL rimegepant exposure is provided descriptively by treatment group/OL rimegepant and 
overall for the DB or OL rimegepant safety analysis set, and includes the following parameters: 
Time on DB or OL rimegepant (weeks), derived as (DB or OL rimegepant end date  DB or 
OL rimegepant start date + 1)/7  
Time on DB or OL rimegepant (weeks) categories:  12,  24, > 24 
Time on DB or OL rimegepant milestone categories: 
o
 3 months, defined as  11 weeks 
o
 6 months, defined as  23 weeks 
o
 1 year, defined as  51 weeks. 
Cumulative DB or OL rimegepant exposure (tablets), derived by summing the number of 
tablets across records with complete dosing date and valid DB rimegepant or OL rimegepant 
wallet number  
Average DB or OL rimegepant exposure (tablets per month), derived as (1) cumulative DB 
or OL rimegepant exposure if time on DB or OL rimegepant < 14 days, or (2) 4 × cumulative 
DB or OL rimegepant exposure/time on DB or OL rimegepant if time on DB or OL 
rimegepant  
14 days  


 
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Total DB or OL rimegepant exposure (tablets) summed across all subjects, derived by 
summing cumulative DB or OL exposure across all subjects 
Total DB or OL rimegepant exposure (patient-years), derived by summing (DB or OL 
rimegepant end date DB or OL rimegepant start date + 1)/365.25 across all subjects. 
6.2.6.2 
Measurements of Treatment Compliance 
 
The by-subject listing of DB treatment compliance is provided for the safety analysis set, and 
displays results for DB treatment compliance parameters in separate columns: average DB 
exposure (tablets per month; see Section 6.2.6.1); percentage for DB tablet count compliance and 
 
The frequency table of DB treatment compliance is provided by treatment group for the safety 
analysis set, and displays the following categories: 
DB study drug taken but not randomized  
DB tablet count compliance  80% from DB study drug start to later of last scheduled DBT 
Phase visit or DB study drug end/OL rimegepant start. Tablet count compliance is derived as 
100 × cumulative DB exposure/required cumulative DB exposure, where 
Cumulative DB exposure is defined in Section 6.2.6.1. 
Required cumulative DB exposure is derived as follows: 
Let n = DB maxdate  DB study drug start date + 1. 
DB maxdate is defined as the latest of the (1) Week 2, 4, 8, and 12 visit dates 
from the Visit Date  DB CRFs, (2) Week 52/EOT visit date from the Visit Date 
 OL CRF, if it is in the DBT safety analysis period (see Section 7.2), and (3) DB 
study drug end date.  
 
If n is even, then the required cumulative DB exposure is n/2.
If n is odd, then the required cumulative DB exposure is n/2 + 1. 
Average DB exposure (tablets per month) categories: 
> 16.8 (> 20% above EOD dosing)
> 15.4 (> 10% above EOD dosing)
 12.6 to  15.4 (  10% of EOD dosing)
 11.2 to  16.8 (  20% of EOD dosing)
 12.6 (  90% compliant with EOD dosing) 
 11.2 (  80% compliant with EOD dosing) 


 
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Average exposure is defined in Section 6.2.6.1. 
DB tablets taken per month for 3 consecutive months categories:  12,  13, and  14 
Tablets per month are assessed by the number of 4-week (28-day) intervals in which a 
subject exceeded select tablet counts from the DB study drug start date to the DB study 
drug end date, where the number of 4-week intervals are consecutive (see Section 6.3.1.1 
for months). For example, suppose a subject takes 20 tablets through 4 weeks, 10 tablets 
after 4 weeks to 8 weeks, and 25 tablets after 8 weeks to 12 weeks. Thus, this subject is 
not considered to have taken  14 tablets (more than EOD frequency) per month for 3 
consecutive months.  
> 1 DB tablet taken on any 1 day 
 1 non-scheduled DB study drug dosing day (see Section 9.4) 
Incorrect DB study drug taken 
All the time. Defined as as-treated treatment group not equal to as-randomized treatment 
group, i.e., any of the following: 
Subjects randomized to rimegepant who took (1)  1 tablet from a DB placebo wallet, 
and (2) no tablets from a DB rimegepant wallet 
Subjects randomized to placebo who took (1)  1 tablet from a DB rimegepant wallet, 
and (2) no tablets from a DB placebo wallet. 
At least once. Defined as any of the following: 
Subjects randomized to rimegpant who took  1 tablet from a DB placebo wallet 
Subjects randomized to placebo who took  1 tablet from a DB rimegepant wallet. 
Time on study drug > 14 weeks. 
  
 
  
The by-subject listing of OL rimegepant treatment compliance is provided for the safety analysis 
set, and displays results for OL rimegepant treatment compliance parameters in separate 
columns: average DB exposure (tablets per month; see Section 6.2.6.1); percentage for OL 
rimegepant 
 
The frequency table of OL rimegepant treatment compliance is provided by treatment group for 
the safety analysis set, and displays the following categories: 
OL rimegepant tablet count compliance   80% from OL rimegepant start to later of last 
scheduled OLE Phase visit or OL rimegepant end. Tablet count compliance is derived as 100 
× cumulative OL rimegepant exposure/required cumulative OL rimegepant exposure, where 
Cumulative OL rimegepant exposure is defined in Section 6.2.6.1. 
Required cumulative OL rimegepant exposure is derived as follows: 


 
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Let n = OL maxdate  OL rimegepant start date + 1. 
OL maxdate is defined as the latest of the (1) Week 14, 16, 20, 24, 28, 32, 36, 40, 
44, and 48 visit dates from the Visit Date  OL CRFs, (2) Week 52/EOT visit date 
from the Visit Date  OL CRF, if it is in the OL rimegepant safety analysis period 
(see Section 7.2), and (3) OL rimegepant end date. 
If n is even, then the required exposure is n/2. 
If n is odd, then the required exposure is n/2 + 1. 
Average OL rimegepant exposure (tablets per month) categories:  14, > 14 to  16, > 16,   
17, > 17, > 18, > 19, > 20, > 22, > 24, > 26. Categories with 0 counts overall are not 
displayed. Average OL rimegepant exposure is defined in Section 6.2.6.1. 
> 1 OL rimegepant tablet taken on any 1 day 
Time on OL rimegepant > 44 weeks 
OL rimegepant start on or before DB study drug end. Defined as nonmissing OL rimegepant 
start date on or before DB study drug end date. 
OL rimegepant taken but DB study drug never taken. Defined as nonmissing OL rimegepant 
start date and missing DB study drug start date.
  
eDiary Usage Compliance  
eDiary Usage Compliance during the OP and DBT Phase 
The table of eDiary usage compliance during the OP and DBT Phase is provided by treatment 
group for the DBT safety analysis set.   
eDiary DBT usage compliance is derived as follows:  
  
eDiary DBT usage compliance is summarized as a continuous variable, and as the number and 
percentage of subjects in the following categories:  90% compliance; 
80% compliance.   
In addition, the number and percentage of subjects with  24 days of eDiary efficacy data in the 
first 28 days of the OP are also provided; see Section 7.2 for the 28-day OP analysis period and 
Section 9.2.2 for eDiary efficacy data days.  
eDiary Usage Compliance during the OLE Phase 
The table of eDiary usage compliance during the OLE Phase is provided by treatment group/OL 
rimegepant and overall for the OL rimegepant safety analysis set.   


 
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eDiary OLE usage compliance is derived as follows:  
  
eDiary OLE usage compliance is summarized as a continuous variable, and as the number and 
percentage of subjects in the following categories:  90% compliance; 
80% compliance.  
6.2.6.3 
Non-study Concomitant Medications 
Refer to the Core SAP for the following: definitions of select non-study medication types (i.e., 
previous, current, DBT concomitant, OL rimegepant concomitant, or follow-up); counting rules 
in non-study medication frequency tables; and non-study medication start and end date 
imputation. 
  
The by-subject listing of non-study medications is provided by therapeutic class and preferred 
name for the enrolled analysis set. Acute migraine and prophylactic migraine medications are 
identified, as well as medication type.  
 
The following conventions apply to non-study medications:  
Non-study medications are identified from those reported on the Concomitant Medication 
CRF. The Concomitant Medication CRF links medical history and AE terms respectively to 
the Medical History and AE CRFs.  
 
Acute migraine medications are defined as those 
. 
Migraine standard of care medications are defined as acute migraine or prophylactic migraine 
medications.
  
  
 
Frequency tables of the following non-study DBT concomitant medications are provided by 
treatment group for the DBT safety analysis set: all; migraine standard of care; prophylactic 
migraine. Medications are displayed in descending order of rimegepant frequency within 
therapeutic class and preferred name.  
Non-study OL Rimegepant Concomitant Medications  
 
Frequency tables of the following non-study OL rimegepant concomitant medications are 
provided by treatment group and overall for the OL rimegepant safety analysis set: all; migraine 
standard of care; prophylactic migraine. Medications are displayed in descending order of overall 
frequency within therapeutic class and preferred name.  


 
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6.3
Efficacy
 
Efficacy endpoints are assessed by as-randomized treatment group.   
Randomization is stratified by prior prophylactic migraine medication use (i.e., randomization 
stratum; yes or no).  Hence, treatment group comparisons of continuous efficacy endpoints are 
adjusted by the randomization stratum, whereas treatment group comparisons of binary efficacy 
endpoints are stratified by the randomization stratum. If there is sparse data within a stratum, 
then results may be presented unstratified. Randomization is stratified using IWRS, but the 
randomization stratum used in analyses is based on actual data (i.e., stable prophylactic migraine 
medication use through randomization; see Sections 4.3 and 6.2.5.4). The rationale for using the 
actual data in analyses is that sites may erroneously report the wrong stratum in IWRS. Note that 
the phrase 
IWRS, throughout this section. 
 
  
  
 
The by-subject listing of primary and secondary efficacy endpoints is provided for the full 
analysis set, and includes the reason for exclusion from the DBT migraine analysis set (see 
Sections 6.3.1 and 6.3.2): randomized more than once; not treated with study drug; treated with 
study drug and < 14 days of eDiary efficacy data in the OP; treated with study drug and < 14 
days of eDiary efficacy data in all 3 months of the DBT Phase. Results for continuous endpoints 
are based on observed data, whereas results for binary endpoints incorporate missing data 
imputation. Subjects with 
14 days of efficacy data (not necessarily consecutive) in the month 
defining the endpoint are flagged for endpoints based on a single month. 
6.3.1 
Reduction in Migraine Days per Month 
Subjects are instructed to report headache occurrence, headache pain features and associated 
symptoms, aura occurrence, and medication used to treat headache or aura in the eDiary 
headache report every day in the OP, DBT, and OLE Phases. 
-
week visit schedule. Migraine days per month are based on 4-week intervals, and are prorated to 
account for missing migraine reports. 
See Section 9.2.2 for the definition of eDiary efficacy data days, and Section 9.2.5 for the 
definition of migraine days.  


 
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6.3.1.1 
Reduction in Migraine Days per Month in the DBT Phase: Primary Efficacy 
Endpoint 
The number of migraine days per month in the DBT phase is examined relative to the number of 
migraine days per month in the OP for the DBT migraine analysis set, i.e., subjects with  14 
days of eDiary efficacy data (not necessarily consecutive) in both the OP analysis period and  1 
month (i.e., 4-week interval) in the on-DBT efficacy analysis period.  
Months in the DBT phase are defined as follows:  
Month 1 (  4 weeks; study days 1 to 28) 
Month 2 (> 4 to  8 weeks; study days 29 to 56) 
Month 3 (> 8 to 
12 weeks; study days 57 to 84).
Analyses are based on eDiary efficacy dates in the OP and on-DBT efficacy analysis periods.  
The number of migraine days per month is prorated to 28 days and derived as follows: 
OP: 28 × (total number of migraine days in the OP analysis period)/(total number of efficacy 
data days in the OP analysis period). Subjects must have  14 days of eDiary efficacy data 
(not necessarily consecutive) in the OP to be evaluable. 
Month (i.e., 4-week interval) in the on-DBT efficacy analysis period: 28 × (total number of 
migraine days in the month)/(total number of efficacy data days in the month). Subjects must 
have  14 days of efficacy data (not necessarily consecutive) in the specified month to be 
evaluable. 
Overall DBT: 28 × (total number of migraine days through Month 3 in the on-DBT efficacy 
analysis period)/(total number of efficacy data days through Month 3 in the on-DBT efficacy 
analysis period). 
Missing Efficacy Data 
The frequency table of missing efficacy data in the OP and DBT Phase is provided for theDBT 
efficacy analysis set, and displays the following categories:  
Included in the DBT migraine analysis set:  14 days of eDiary efficacy data (not necessarily 
consecutive) in both the OP and  1 month (i.e., 4-week interval) of the DBT Phase 
o
Month 1:  4 weeks * 
o
Month 2: > 4 to  8 weeks * 
o
Month 3: > 8 to  12 weeks * 
Excluded from the DBT migraine analysis set 
o
< 14 days of eDiary efficacy data in the OP  
o
< 14 days of eDiary efficacy data in all 3 months of the DBT Phase. 


 
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 14 days of efficacy data (not necessarily 
consecutive) in the specified month to be evaluable. 
Descriptive Analyses  
The table of values and changes (both absolute and percent) from the OP in the number of 
migraine days per month in the DBT Phase is provided for the DBT migraine analysis set, and 
summarizes parameters descriptively as continuous variables (including 2-sided normal 95% CIs 
for mean change) by treatment group and by pain intensity in each month of the DBT Phase and 
overall DBT. Pain intensity categories are (1) total (mild, moderate, severe, none, or not 
reported) and (2) moderate or severe. The table also presents results by subgroup level for all 
efficacy subgroups of interest described in Section 4.3. 
In the percent change analyses, subjects must also have  1 migraine day (i.e., absolute not 
prorated to 28 days) of appropriate migraine severity in the OP analysis period to be included. 
Treatment Group Comparisons  
Analyses are based on DBT migraine analysis set and total pain intensity, unless otherwise 
specified.  
Main Analysis: DBT Migraine Analysis Set   
The main analysis of the primary endpoint uses a linear mixed effects model with repeated 
measures and the following attributes: 
Variables: change from the OP in number of total migraine days per month as the dependent 
variable; number of total migraine days per month in the OP as a covariate; treatment group, 
randomization stratum, month (i.e., Months 1 to 3 of the DBT Phase), and the month-by-
treatment group interaction as fixed effects. 
Covariance structure for repeated measures accounting for within-subject correlated errors: 
assumed to be homogeneous across treatment groups and initially specified as unstructured. 
If the model fails to converge or cannot be fit with an unstructured covariance structure, then 
other covariance structures are specified in the following hierarchical order: Toeplitz (which 
has heterogenous variances and heterogenous correlations between elements); first-order 
autoregressive with heterogeneous variances; and first-order autoregressive with 
homogeneous variances.
SE estimation method: Huber-White robust sandwich  (refer to the Core SAP). 
The table displays the following model estimates: 
Least-squares mean (LSM) change from OP, standard error (SE), and 95% CI by month and 
overall DBT for each treatment group  
Difference in LSM changes from OP between rimegepant and placebo, SE, 95% CI, and p-
value at each month and overall DBT. Results in the last month support the primary 
objective, results in the overall DBT support secondary objective #2, results in the first 


 
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month support secondary objective #3, and results in the second month support exploratory 
objective #1. 
See Section 9.3.1 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional linear mixed effects models that exclude 
randomization stratum as a fixed effect. 
The main analyses are repeated for moderate or severe pain intensity to support exploratory 
objective #1. All variables in the model are the same, except (1) change from the OP in number 
of moderate or severe migraine days per month is the dependent variable, and (2) number of 
moderate or severe migraine days per month in the OP is the covariate. The corresponding table 
has the same format. 
The line plot displays the LSM change from OP in the number of total migraine days from OP 
per month on the y-axis versus month of the DBT Phase on the x-axis by treatment group. Error 
bars denote 95% CIs. 
J2R Imputation Sensitivity Analysis: DBT Efficacy Analysis Set  
A sensitivity analysis of the primary endpoint uses the same linear mixed effects model as the 
main analysis, but with jump to reference (J2R) to impute missing data (i.e., change from OP in 
the number of total migraine days per month) in Months 1 to 3 for the DBT efficacy analysis set. 
 
The analysis is performed using the following steps: 
1)
1 2  
a)
 
b) Data imputation is applied to each treatment group. 
c) The imputation model uses the following variables: number of total migraine days per 
month in the OP, age, sex, randomization stratum, and treatment group.  
d) The macros are run in the following order: %part1A; %part1B using n = 200 data sets 
(Ndraws parameter) and n = 100 for Markov chain Monte Carlo (MCMC) chain thinning 
(thin parameter); %part2A; and %part2B. Note that Ndraws and thin parameters may be 
modified as needed (e.g., to decrease MCMC error and autocorrelation). 
2) Each imputed data set in step 1 is analyzed using the same model from the main analysis (see 
Section 9.3.1).
3) Results from each model analysis in step 2 are combined to produce a pooled difference in 
LSM change, SE, 95% CI, and p-value using SAS proc mianalyze. 
The corresponding table has the same format as the one for the main analysis. 
Tipping Point Sensitivity Analysis: DBT Efficacy Analysis Set 


 
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A tipping point sensitivity analysis is performed for the DBT efficacy analysis set, and only if 
the p-value  0.05 for the treatment group comparison for the main analysis of the last 4 weeks 
of the DBT Phase. 
The analysis is performed using the following steps: 
1)
a)
 
i)
 
ii) Data imputation is applied to each treatment group. 
iii) The fully conditional specification (FCS) method is used with regression to impute 
data at Months 1 to 3. 
iv) The imputation model specifies variables in the following order: changes from OP in 
the number of total migraine days per month at Months 1 to 3, number of total 
migraine days per month in the OP, age, sex, randomization stratum, and treatment 
group. 
v) A shift of is applied to imputed data only for subjects in the rimegepant treatment 
group.
b) Each imputed data set in step 1a is analyzed using the same model from the main analysis 
(see Section 9.3.1). 
c) Results from each model analysis in step 1b are combined to produce a pooled difference 
in LSM change, SE, 95% CI, and p-value using SAS proc mianalyze. 
2) The p-value for the treatment group comparison of the last 4 weeks of the DBT Phase 
compared to 0.05.  
a) If p-value 0.05, then is incremented by 0.1, and step 1 is repeated.
b) If p-value > 0.05, then the iterative process stops, and the last  used becomes the tipping 
point. 
For each shift parameter, the same statistics are provided as those in the main analysis, but only 
for the last 4 weeks of the DBT Phase. Results across all shift parameters are displayed together 
in the same table. 
Subgroup Analyses 
Subgroup analyses of the primary endpoint will use the same linear mixed effects model 
specified for the main analysis of the primary endpoint. The following model estimates will be 
reported by subgroup of historical chronic migraine according to ICHD 3rd edition (yes or no) 
(Section 4.3). P-values are presented only for descriptive purpose. 


 
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LSM change from OP, SE, 95% CI by month in the DBT Phase and overall DBT for each 
treatment group 
Difference in LSM changes from OP between treatment groups (rimegepant - placebo), SE, 
95% CI, and p-value at each month and overall DBT.  
6.3.1.2 
Reduction in Migraine Days per Month in the OLE Phase 
The number of migraine days per month in the OLE Phase is examined relative to the number of 
migraine days per month in the OP for the OL rimegepant migraine analysis set, i.e., subjects 
with  14 days of eDiary efficacy data (not necessarily consecutive) in the OP analysis period,  
1 month (i.e., 4-week interval) in the on-DBT efficacy analysis period, and 
1 month in the on-
OL rimegepant efficacy analysis period.  
Months in the OLE Phase are defined as:  
Month 1 (> 12 to  16 weeks; study days 85 to 112) 
Month 2 (> 16 to  20 weeks; study days 113 to 140) 
Month 3 (> 20 to  24 weeks; study days 141 to 168) 
Month 4 (> 24 to  28 weeks; study days 169 to 196) 
Month 5 (> 28 to  32 weeks; study days 197 to 224) 
Month 6 (> 32 to  36 weeks; study days 225 to 252) 
Month 7 (> 36 to  40 weeks; study days 253 to 280) 
Month 8 (> 40 to  44 weeks; study days 281 to 308) 
Month 9 (> 44 to  48 weeks; study days 309 to 336) 
Month 10 (> 48 to  52 weeks; study days 337 to 364). 
Analyses are based on eDiary efficacy dates in the OP analysis period and on-OL rimegepant 
efficacy analysis period. 
The number of migraine days per month are to 28 days, and derived as follows: 
OP: See Section 6.3.1.1. 
Month (i.e., 4-week interval) in the on-OL rimegepant efficacy analysis period: 28 × (total 
number of migraine days in the month)/(total number of efficacy data days in the month). 
Subjects must have  14 days of eDiary efficacy data (not necessarily consecutive) in the 
specified month to be evaluable. 
Overall OL rimegepant: 28 × (total number of migraine days through Month 10 in the on-OL 
rimegepant efficacy analysis period)/(total number of efficacy data days through Month 10 in 
the on-OL rimegepant efficacy analysis period). 
Missing Efficacy Data  


 
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The frequency table of missing efficacy data in the OP and OLE Phase is provided for the OL 
rimegepant efficacy analysis set by treatment group/OL rimegepant and overall, and displays the 
following categories:  
Included in the OL rimegepant migraine analysis set:  14 days of eDiary efficacy data (not 
necessarily consecutive) in the OP,  1 month (i.e., 4-week interval) of the DBT Phase, and  
1 month of the OLE Phase 
o
Month 1: > 12 to  16 weeks * 
o
Additional months defined previously 
o
Month 10: > 48 to  52 weeks * 
Excluded from the OL rimegepant migraine analysis set
o
< 14 days of eDiary efficacy data in the OP  
o
< 14 days of eDiary efficacy data in all 3 months of the DBT Phase (see Section 6.3.1.1) 
o
< 14 days of eDiary efficacy data in all 10 months of the OLE Phase.
 14 days of eDiary efficacy data (not 
necessarily consecutive) in the specified month to be evaluable. 
Descriptive Analyses 
Analyses are based on the OL rimegepant migraine analysis set, unless otherwise specified.  
The table of values and changes (both absolute and percent) from the OP in the number of 
migraine days per month in the OLE Phase is provided, and summarizes parameters descriptively 
as continuous variables (including 2-sided 95% CIs for mean change) by treatment group/OL 
rimegepant and overall and by pain intensity (total; moderate or severe) in each month of the 
OLE Phase and overall OL rimegepant. Results support exploratory objective #4.  
A line plot displays the mean change from OP in the number of total migraine days per month on 
the y-axis versus month (Month 1 to 10) of the OLE Phase on the x-axis by treatment group/OL 
rimegepant. Another line plot displays the mean change from OP in the number of total migraine 
days per month on the y-axis versus month (Month 1 to 13) of the DBT and OLE Phases on the 
x-axis for the DBT migraine analysis set by (1) treatment group during the DBT Phase and (2) 
overall for the OLE Phase. Error bars denote 95% CIs. 
In the percent change analyses, subjects must also have  1 migraine day (i.e., absolute not 
prorated to 28 days) of appropriate severity in the OP analysis period to be included. 


 
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6.3.2 
Secondary Efficacy Endpoints 
6.3.2.1 
Percentages of Subjects with Reduction in Number of Migraine Days per 
Month
In analyses by months, subjects must (1) achieve the reduction criterion from OP in the number 
of migraine days in the specified month, (2) be evaluable (i.e., have  14 days of efficacy data 
[not necessarily consecutive]) in the specified month, and (3) have  1 migraine day (absolute 
not prorated to 28 days) of appropriate migraine severity in the OP analysis period to be 
classified as responders in the specified month. Otherwise, subjects are classified as failures in 
the specified month.  
In analyses of the overall DBT (or overall OLE), subjects must (1) achieve the reduction 
criterion from OP in the number of migraine days in the overall DBT (or overall OLE), and (2) 
have  1 migraine day (absolute not prorated to 28 days) of appropriate migraine severity in the 
OP analysis period to be classified as responders. Otherwise, subjects are classified as failures.  
Percentages of Subjects with Reduction in Migraine Days per Month in the DBT Phase  
Analyses are based on the DBT migraine analysis set with eDiary efficacy dates in the OP and 
on-DBT efficacy analysis periods (see Section 6.3.1.1). 
Treatment Group Comparisons 
For each pain intensity (total; moderate or severe) and select percentage reductions (  50%,  
75%, and 100%), the percentages of subjects with reductions are compared between treatment 
groups using Mantel-Haenszel risk estimation with stratification by randomization stratum (yes, 
no). This may be accomplished using SAS proc stdrate with the following options: method=mh, 
stat=risk, and effect=diff. Percentages are calculated against the number of subjects in the DBT 
migraine analysis set. 
The table displays the following statistics at each month of the DBT Phase and overall DBT by 
pain intensity: 
 
Stratified percentage difference between treatment groups (rimegepant  placebo), ASE, 95% 
CI, and p-value 
each treatment group  
Percentage difference between treatment groups (rimegepant  placebo), ASE, 95% CI, and 
p-value by randomization stratum. 
Results for 
50% reduction of moderate or severe migraine severity in the last 4 weeks (i.e., 
Month 3) support secondary objective #1. All other results support exploratory objective #2.  
Subgroup analyses 


 
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Proportion of subjects with   50% reduction from baseline in the number of moderate to severe 
migraine days will also be compared between treatment groups using a Mantel-Haenszel risk 
estimation with stratification by randomization stratum (yes, no) by subgroup of historical 
chronic migraine according to ICHD 3rd edition (yes or no) (Section 4.3). P-values are presented 
only for descriptive purpose. 
The following statistics will be presented for each month in the DBT Phase and overall DBT 
mean by subgroup of historical chronic migraine according to ICHD 3rd edition (yes or no): 
Response rate (
), ASE, and 95% CI for each treatment group 
Stratified percentage difference between treatment groups (rimegepant  placebo), ASE, 95% 
CI, and p-value. 
Percentages of Subjects with Reduction in Migraine Days per Month in the OLE Phase  
Analyses are based on the OL rimegepant migraine analysis set with eDiary efficacy dates in the 
OP and on-OL rimegepant efficacy analysis periods.  
The frequency table of reductions from the OP in the number of migraine days per month in the 
OLE Phase is provided by treatment group/OL rimegepant and overall and by pain intensity 
(total; moderate or severe) in each month of the OLE Phase and overall OLE (see Section 6.3.1.2 
for months), and displays the number and percentage of evaluable subjects in the following 
reduction categories:  50%,  75%, and 100%. Percentages are calculated against the number of 
evaluable subjects in the OL rimegepant migraine analysis set:  
In analyses by month, evaluable subjects are those with  1 migraine day of appropriate pain 
intensity in the OP and  14 days of eDiary efficacy data in the specified month.  
In analyses of the overall OLE, evaluable subjects are those with  1 migraine day of 
appropriate pain intensity in the OP. 
Results support exploratory objective #5.
6.3.2.2 
Acute Migraine-specific Medication Days per Month 
During the DBT and OLE Phases, subjects may record taking triptan, ergotamine, and other 
medications to treat headache or during aura in the eDiary headache report. 
Acute migraine-
-specific 
-week visit schedule. Acute migraine-
specific medication days per month are based on 4-week interval, and are prorated to account for 
missing migraine reports. See Section 9.2.4 for the definition of acute migraine-specific 
medication day. 
Acute Migraine-specific Medication Days per Month in the DBT Phase  
Analyses are based on the DBT migraine analysis set with eDiary efficacy dates in the on-DBT 
efficacy analysis period.  


 
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The number of acute migraine-specific medication days per month in the DBT phase is prorated 
to 28 days and derived as follows:  
Month (i.e., 4-week interval) in the on-DBT efficacy analysis period: 28 × (total number of 
acute migraine-specific medication days in the month)/(total number of efficacy data days in 
the month). Subjects must have  14 days of efficacy data (not necessarily consecutive) in 
the specified month to be evaluable. 
Overall DBT: 28 × (total number of acute migraine-specific medication days through Month 
3 in the on DBT efficacy analysis period)/(total number of efficacy data days through Month 
3 in the on DBT efficacy analysis period).  
Descriptive Analyses  
The table of the number of acute migraine-specific medication days per month in the DBT Phase 
is provided, and summarizes the parameter descriptively as a continuous variable (including 2-
sided normal 95% CIs for mean) by treatment group in each month of the DBT Phase and overall 
DBT. 
Treatment Group Comparisons  
Treatment groups are compared using a linear mixed effects model with repeated measures and 
the following attributes: 
Variables: number of acute migraine-specific medication days per month as the dependent 
variable; treatment group, randomization stratum, month (i.e., Months 1 to 3 of the DBT 
Phase), and the month-by-treatment group interaction as fixed effects 
Covariance structure for repeated measures accounting for within-subject correlated errors: 
See Section 6.3.1.1. 
 SE estimation method: See Section 6.3.1.1. 
The table displays the following model estimates: 
LSM, SE, and 95% CI by month and overall DBT for each treatment group 
Difference in LSMs between treatment groups (rimegepant  placebo), SE, 95% CI, and p-
value at each month and overall DBT. Results in the last 4 weeks support secondary 
objective #4, whereas results at other time points support exploratory objective #6. 
Model estimates by randomization stratum (yes, no) are presented in the same table, using 
additional models that exclude randomization stratum as a fixed effect.  
Subgroup Analyses 
Subgroup analyses of the acute migraine-specific medication days will use the same linear mixed 
effects model specified above. The following model estimates will be reported by subgroup of 
historical chronic migraine according to ICHD 3rd edition (yes or no) (Section 4.3). P-values are 
presented only for descriptive purpose. 
LSM, SE, and 95% CI by month in the DBT Phase and overall DBT for each treatment group 


 
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Difference in LSMs between treatment groups (rimegepant - placebo), SE, 95% CI, and p-
value by month and overall DBT. 
Acute Migraine-specific Medication Days per Month in the OLE Phase  
Analyses are based on the OL rimegepant migraine analysis set with eDiary efficacy dates in the 
on-OL rimegepant efficacy analysis period.  
The number of acute migraine-specific medication days per month in the OLE Phase is prorated 
to 28 days and derived as follows:  
Month (i.e., 4-week interval) in the on-OL rimegepant efficacy analysis period: 28 × (total 
number of acute migraine-specific medication days in the month)/(total number of efficacy 
data days in the month). Subjects must have  14 days of efficacy data (not necessarily 
consecutive) in the specified month to be evaluable. 
Overall OL rimegepant: 28 × (total number of acute migraine-specific medication days 
through Month 10 in the on-OL rimegepant efficacy analysis period)/(total number of 
efficacy data days through Month 10 in the on-OL rimegepant efficacy analysis period).  
The table of the number of acute migraine-specific medication days per month in the OLE Phase 
is provided, and summarizes the parameter descriptively as a continuous variable (including 2-
sided normal 95% CIs for mean) by treatment group/OL rimegepant and overall in each month 
of the OLE Phase and overall OL rimegepant.  
Results support exploratory objective #7.
6.3.2.3 
Overall Summary of Primary and Secondary Endpoints in Hierarchical 
Testing 
The overall summary table of treatment comparisons of all primary and secondary endpoints 
tested hierarchically displays the following statistics: 
Continuous endpoints involving change from OP or baseline  
n (i.e., number of subjects in the analysis set), overall LSM change and 95% CI for each 
treatment group  
Difference in overall LSM changes between treatment groups (rimegepant  placebo), 
95% CI, and p-value.  
This applies to the primary endpoint and the following secondary efficacy and outcomes 
endpoints: mean change in the number of migraine days per month in the overall DBT Phase 
(see main analysis in Section 6.3.1.1); mean change in the number of migraine days per 
month in the first month of the DBT Phase (see main analysis in Section 6.3.1.1); MSQoL 
restrictive role domain score change from baseline at Week 12 (see Section 6.5.1); MIDAS 
total score change from baseline at Week 12 (see Section 6.5.2); and EQ-5D-5L VAS score 
change from baseline at Week 12 (see Section 6.5.3). 
Continuous endpoints not involving change from OP or baseline 


 
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n, overall LSM and 95% CI for each treatment group 
Difference in overall LSMs between treatment groups (rimegepant  placebo), 95% CI, 
and p-value.  
This applies to the secondary efficacy endpoint of the mean number of acute migraine-specific 
medication days per month in the last month of the DBT Phase (see Section 6.3.2.2).  
Binary endpoints 
 
Stratified percentage difference between treatment groups (rimegepant  placebo), 95% 
CI, and p-value.  
This applies to the secondary efficacy endpoint of the percentage of subjects with  50% 
reduction in the mean number of moderate or severe migraine days per month in the last 
month of the DBT Phase (see Section 6.3.2.1).  
Endpoints are displayed in the order presented in Sections 3.2.1 and 3.2.2. P-values that are 
determined to be significant based on the testing hierarchy are flagged. 
If the primary endpoint is significant, then the secondary efficacy and outcomes research 
endpoints are tested hierarchically, each at a 2-sided alpha level of 0.05, in the order specified in 
Section 3.2.2. Thus, a secondary efficacy or outcomes research endpoint is tested only if the 
preceding secondary endpoint in the hierarchy is determined to be significant (i.e., p-value  
0.05). If a test in the hierarchy is not significant, then any further tests on endpoints in the 
sequence have p-values presented only for descriptive purposes, and no conclusions are drawn 
from those results. 
For a given treatment comparison of a continuous endpoint, the null hypothesis of interest H0 is 
that the mean change observed on rimegepant (denoted 
rimegepant) is equal to the one observed on 
placebo (denoted
placebo), i.e., H0: 
rimegepant = 
placebo. The alternative 2-sided hypothesis of 
interest H1 is that the mean changes observed on rimegepant and placebo differ, i.e., H1: 
rimegepant  
placebo. For a given treatment comparison of a binary endpoint, the hypotheses are 
based on percentages instead of mean changes. 
6.3.3 
Exploratory Efficacy Endpoints 
For exploratory efficacy endpoints, no attempt is made to adjust for multiplicity. Any 
exploratory endpoints for which p-values are produced are evaluated at an unadjusted, 2-sided 
alpha level of 0.05 and presented only for descriptive purposes. 
 
This section also includes analyses of endpoints based on headache days that are typically 
included for migraine prevention studies. These are not formally prespecified in Section 3.2.3. 
6.3.3.1 
Reduction in Number of Headache Days per Month in the DBT Phase 


 
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In the percent change analyses, subjects must also have  1 headache day (absolute not prorated) 
of appropriate pain intensity in the OP analysis period to be included. 
 
 
Analyses are based on the DBT migraine analysis set with eDiary efficacy dates in the OP and 
on-DBT efficacy analysis periods. 
 
 
The table of values and changes (both absolute and percent) from the OP in the number of 
headache days per month in the DBT Phase is provided, and has the same format as the one 
described in Section 6.3.1.1. 
 
 
Treatment groups are compared using a linear mixed effects model with repeated measures with 
the same attributes as the one for the primary endpoint except that change from the OP in 
number of total headache days per month is the dependent variable. The table has the same 
format as the one described in Section 6.3.1.1. 
These analyses are repeated for moderate or severe headache pain intensity. All variables in the 
model are the same, except change from the OP in number of moderate or severe headache days 
per month is the dependent variable. The table has the same format. 
 
 
Analyses are based on the OL rimegepant migraine analysis set with eDiary efficacy dates in the 
OP and on-OL rimegepant efficacy analysis periods. 
The table of values and changes (both absolute and percent) from the OP in the number of 
headache days per month in the OLE Phase is provided, and has the same format as the one 
described in Section 6.3.1.2. 
6.3.3.2 
Percentages of Subjects with Reduction in Number of Headache Days per 
Month in the DBT Phase 
The percentages of subjects with reduction in the number of headache days during the DBT and 
OLE Phases are defined and assessed analogously to the percentages of subjects with reduction 
in the number of migraine days during the DBT and OLE Phases (see in Section 6.3.2.1). 
Percentages of Subjects with Reduction in Headache Days per Month in the DBT Phase  


 
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Analyses are based on the DBT migraine analysis set with eDiary efficacy dates in the OP and 
on-DBT efficacy analysis periods. 
For each pain intensity and select percentage reduction, the percentages of subjects with 
reductions from the OP in the number of headache days per month in the DBT Phase are 
compared between treatment groups using Mantel-Haenszel risk estimation with stratification by 
randomization stratum (yes, no). The table has the same format as the one described in Section 
6.3.2.1. 
Percentages of Subjects with Reduction Headache Days per Month in the OLE Phase  
Analyses are based on the OL rimegepant migraine analysis set with eDiary efficacy dates in the 
OP and on-OL rimegepant efficacy analysis periods.  
The frequency table of reductions from the OP in the number of headache days per month in the 
OLE Phase is provided, and has the same format as the one described in Section 6.3.2.1.
6.3.3.3 
Reduction in the Number of Migraine Days per Week and Headache Days 
per Week in the First Month of the DBT Phase 
The number of migraine days per week in the first month (Weeks 1 to 4) of the DBT Phase is 
examined relative to the number of migraine days per week in the OP for the DBT first month 
migraine analysis set, i.e., subjects in the DBT efficacy analysis set with  24 days of eDiary 
efficacy data (not necessarily consecutive) in both the OP analysis period and first month of the 
on-DBT efficacy analysis period.  
Weeks 1 to 4 of the DBT Phase are defined as follows: 
Week 1: study days 1 to 7 
Week 2: study days 8 to 14 
Week 3: study days 15 to 21 
Week 4: study days 22 to 28. 
See Sections 7.2 and 7.3 for the definition of analysis periods and study days used to define 
analysis visit windows.  
Analyses are based on the DBT first month migraine analysis set using eDiary efficacy dates in 
the OP and on-DBT efficacy analysis periods. 
The number of migraine days per week is prorated to 7 days and derived as follows: 
OP: 7  (total number of migraine days in the OP analysis period)/(total number of eDiary 
efficacy data days in the OP analysis period) 
Week (7-day interval) of the on-DBT efficacy analysis period: 7  (total number of migraine 
days in the week)/(total number of eDiary efficacy data days in the week). 


 
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The number of headache days per week is derived analogously. 
Descriptive Analyses 
The table of values and changes (both absolute and percent) from the OP in the number of 
migraine days per week in the first month (Weeks 1 to 4) of the DBT Phase is provided, and 
summarizes parameters descriptively as continuous variables (including 2-sided normal 95% CIs 
for mean change) by treatment group and pain intensity (total; moderate or severe). In the 
percent change analyses, subjects must also have 
1 migraine day of appropriate intensity 
(absolute not prorated) in the OP analysis period to be included. 
Treatment Group Comparisons 
Treatment groups are compared using a linear mixed effects model with repeated measures and 
the following attributes: 
Variables: change from the OP in number of total migraine days per week as the dependent 
variable; number of total migraine days per week in the OP as a covariate; treatment group, 
randomization stratum, week (i.e., Weeks 1 to 4 of the DBT Phase), and the week-by-
treatment group interaction as fixed effects.  
Covariance structure for repeated measures accounting for within-subject correlated errors: 
See Section 6.3.1.1. 
SE estimation method: See Section 6.3.1.1. 
The table displays the following model estimates: 
LSM change from OP, SE, and 95% CI by week for each treatment group 
Difference in LSM changes from OP between treatment groups (rimegepant  placebo), SE, 
95% CI, and p-value for each week.  
See Section 9.3.1 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional linear mixed effects models that exclude 
randomization stratum as a fixed effect.
These analyses are repeated for moderate or severe pain intensity. All variables in the model are 
the same, except (1) change from the OP in number of moderate or severe migraine days per 
week is the dependent variable, and (2) number of moderate or severe migraine days per week in 
the OP is the covariate. The corresponding table has the same format. 
Results support exploratory objective #3. 
All analyses described above are performed analogously for headache days per week. 
6.3.3.4 
Acute Migraine Medication days per Month 
Acute migraine medication days per month are assessed analogously to acute migraine-specific 
medication days per month (see Section 6.3.2.2).   


 
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An acute migraine medication day is defined in Section 9.2.3. 
The number of acute migraine medication days per month in the DBT and OLE Phases is 
prorated to 28 days. 
Acute Migraine Medication Days per Month in the DBT Phase  
Analyses are based on the DBT migraine analysis set with eDiary efficacy dates in the on-DBT 
efficacy analysis period.  
Descriptive Analyses  
The table of the number of acute migraine medication days per month in the DBT Phase is 
provided, and has the same format as the one described in Section 6.3.2.2.
Treatment Group Comparisons  
Treatment groups are compared using a linear mixed effects model with repeated measures with 
the same properties as the model specified in Section 6.3.2.2, except that the number of acute 
migraine medication days per month is the dependent variable.  
Results support exploratory objective #6.
Acute Migraine Medication Days per Month in the OLE Phase  
Analyses are based on the OL rimegepant migraine analysis set with eDiary efficacy dates in the 
on-OL rimegepant efficacy analysis period.  
The table of the number of acute migraine medication days per month in the OLE Phase is 
provided, and has the same format as the one described in Section 6.3.2.2. 
Results support exploratory objective #7.
6.3.3.5 
Medication Days per Month on Planned OL Rimegepant Dosing Days 
This section includes analyses which are not formally prespecified in Section 3.2.3, but are 
typically included for migraine prevention studies with an OLE Phase. 
Planned OL rimegepant dosing days are defined in Section 9.4. Medications are OL rimegepant 
and acute migraine medication. 
For a given medication, the medication days per month on planned scheduled OL rimegepant 
dosing days through Month 10 is calculated as: 14  (total number of medication days on the 
same days as planned scheduled OL rimegepant dosing days through Month 10 in the on-OL 
rimegepant efficacy analysis period)/(total number of planned scheduled OL rimegepant dosing 
days through Month 10 in the on-OL rimegepant efficacy analysis period). 


 
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For a given medication, the medication days per month on planned non-scheduled OL 
rimegepant dosing days through Month 10 is calculated as: 14  (total number of medication 
days on the same days as planned non-scheduled OL rimegepant dosing days through Month 10 
in the on-OL rimegepant efficacy analysis period)/(total number of planned non-scheduled OL 
rimegepant dosing days through Month 10 in the on-OL rimegepant efficacy analysis period). 
The table of medication days per month on planned scheduled OL rimegepant dosing days 
through Month 10 is provided, and summarizes parameters descriptively as continuous variables 
for the OL rimegepant migraine analysis set by treatment group/OL rimegepant and overall for 
the following medications: 
Any medication: rimegepant or acute migraine medication (triptan, ergotamine, or other) 
Rimegepant or acute migraine-specific medication (triptan or ergotamine)
Rimegepant and acute migraine medication 
Rimegepant and acute migraine-specific medication 
Rimegepant only (i.e., no acute migraine medication) 
Acute migraine medication 
Acute migraine medication only (i.e., no rimegepant) 
Acute migraine-specific medication  
Acute migraine-specific medication only (i.e., no rimegepant or other medication) 
Other medication  
Other medication only (i.e., no rimegepant or acute migraine-specific medication). 
The table of medication days per month on planned non-scheduled OL rimegepant dosing days 
through Month 10 is also provided, and summarizes parameters analogously. 
6.4
Safety 
Safety analyses are provided according to analysis period and analysis set:  
On-DBT safety for the DBT safety analysis set by treatment group  
Post-DBT pre-OL rimegepant safety for the interim safety analysis set by treatment group 
and overall  
On-OL rimegepant safety for the OL rimegepant safety analysis set by treatment group/OL 
rimegepant and overall  
On-DB or OL rimegepant safety for the DB or OL rimegepant safety analysis set by 
treatment group/OL rimegepant and overall  
Follow-up safety for the follow-up safety analysis set by treatment group/OL rimegepant 
status and overall.   
Treatment group is as-treated treatment group according to Section 4.2.  


 
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Safety parameters include the following: deaths; AEs; laboratory tests; vital signs; physical 
measurements; electrocardiograms (ECGs); and Columbia-Suicidality Severity Rating Scale (C-
SSRS.  
Measurements are slotted into analysis periods and analysis visits using the following steps:  
1) Measurements are slotted into the pretreatment, on-treatment safety, and follow-up safety 
analysis periods.  
2) Measurements are slotted into analysis visits in the analysis periods listed in the previous step 
(see Table 5). 
3) Measurements in the on-treatment safety analysis period are slotted further into the on-DBT, 
post-DBT pre-OL rimegepant, and on-OL rimegepant safety analysis periods. 
Refer also to the Core SAP for details about measurement slotting. See Sections 6.2.5, 7.2, and 
7.3 for definitions of baseline, analysis periods, and analysis visit windows, respectively.   
6.4.1 
Adverse Events 
Refer to the Core SAP for the following: AE start and end date imputation; death date derivation; 
rules for counting and rounding in frequency tables; definition of AEs of special interest, and 
exposure-adjusted multiple occurrences of unique AEs; and TLF contents. An AE is considered 
to be related to study drug if the relationship to study drug is unlikely related, possibly related, or 
related. 
Frequency tables of AEs by SOC and PT display AEs in descending order of overall frequency 
within SOC and PT, unless otherwise specified. 
The by-subject listing of AEs (i.e., non-SAEs and SAEs) is provided for the enrolled analysis set.  
6.4.1.1 
Deaths 
Deaths are identified from any of the following sources:  
AE CRF with any of the following:
date  
Screening Status CRF: death as reason for screen failure 
DB Subject Status CRF with any of the following: death as reason for DBT Phase non-
completion, or death as reason for not continuing to the next phase 
OLE Subject Status CRF with any of the following: death as reason for OLE Phase non-
completion; death as reason for not continuing to the Follow-up Phase.  
Follow-up Subject Status CRF: death as reason for Follow-up Phase non-completion.  
The by-subject listing of deaths is provided for the enrolled analysis set.  


 
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6.4.1.2 
AE Overviews 
An AE overview frequency table displays the following categories without SOC and PT: any 
AE; mild AE; moderate AE; severe AE; AE related to study drug; AE leading to study drug 
discontinuation; SAE; SAE related to study drug; medication-overuse headache AE; hepatic-
related AE; hepatic-related AE leading to study drug discontinuation; potential drug abuse AE; 
cardiovascular AE; and suicidality AE.   
AE overview frequency tables are provided for the following safety analysis periods and analysis 
sets:  
On-DBT for the DBT safety analysis set  
Post-DBT pre-OL rimegepant for the interim safety analysis set  
On-OL rimegepant for the OL rimegepant safety analysis set  
On-DB or OL rimegepant for the DB or OL rimegepant safety analysis set  
Follow-up for the follow-up safety analysis set.
6.4.1.3 
On-DBT AEs 
Frequency tables of on-DBT AEs are provided by SOC and PT for the DBT safety analysis set 
for the following endpoints:  
AEs by worst intensity (secondary objective #8) 
AEs related to study drug by worst intensity  
AEs by relationship to study drug (related, possibly related, unlikely related, not related, not 
reported)  
SAEs (secondary objective #8) 
AEs leading to study drug discontinuation (secondary objective #8) 
Hepatic-related AEs (secondary objective #9) 
Hepatic-related AEs leading to study drug discontinuation (secondary objective #9) 
Potential drug abuse AEs, displayed in alphabetical order by worst intensity and PT without 
SOC  
Cardiovascular AEs  
Suicidality AEs  
Frequency tables of AEs by SOC and PT display AEs in descending order of rimegepant 
frequency within SOC and PT, unless otherwise specified. 


 
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6.4.1.4 
On-OL Rimegepant AEs 
Frequency tables of on-OL rimegepant AEs by SOC and PT are provided for the OL rimegepant 
safety analysis set for the following endpoints:  
AEs by worst intensity (secondary objective #8)  
AEs related to study drug by worst intensity  
AEs by relationship to study drug (related, possibly related, unlikely related, not related, not 
reported)  
SAEs (secondary objective #8) 
AEs leading to study drug discontinuation (secondary objective #8).  
Hepatic-related AEs (secondary objective #9) 
Hepatic-related AEs leading to study drug discontinuation (secondary objective #9) 
Potential drug abuse AEs, displayed in alphabetical order by worst intensity and PT without 
SOC  
Cardiovascular AEs  
Suicidality AEs  
6.4.1.5 
On-DB or OL Rimegepant AEs 
Frequency tables of on-DB or OL rimegepant AEs by SOC and PT are provided for the DB or 
OL rimegepant safety analysis set for below endpoints: 
AEs by worst intensity (secondary objective #8) 
SAEs (secondary objective #8) 
Exposure-adjusted multiple occurrences of unique AEs. 
Calculations for on-DB or OL rimegepant exposure-adjusted multiple occurrences of unique AEs 
use an analysis period reference start date = DB or OL rimegepant start date, analysis period 
reference end date = DB or OL rimegepant last date + 7 days if the DB or OL rimegepant last 
date is nonmissing, and analysis period reference end date = DB or OL rimegepant end date if 
the DB or OL rimegepant last date is missing. 
6.4.1.6 
Follow-up AEs 
Frequency tables of follow-up AEs are provided by SOC and PT for the follow-up safety 
analysis set for the following endpoints: 
AEs by worst intensity 


 
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SAEs.
6.4.2 
Laboratory Tests 
Results are based on (1) external data from the central laboratory which reports both laboratory 
collection date and time, and (2) local data reported on Urine Pregnancy Test CRFs which 
capture only collection date. TLFs display results in Systeme Internationale (SI) units, if 
applicable. 
Laboratory tests of clinical interest are collected at the following visits:
Hematology: Screening; Baseline; Weeks 4, 8, 12, 24, and 52/EOT   
Serum chemistry: Screening; Baseline; Weeks 4, 8, 12, 24, and 52/EOT. Exceptions are for 
the following:  
LFTs (ALT, AST, ALP, TBL, direct bilirubin, indirect bilirubin): All visits 
Lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density 
lipoprotein [LDL] cholesterol, triglycerides): Baseline; Weeks 24 and 52/EOT  
Urinalysis: Baseline; Week 52/EOT.  
The following by-subject laboratory test listings are provided for the enrolled analysis set:  
Laboratory test results (SI units). The listing displays all test results over time for subjects 
with select findings (grade 3 to 4 laboratory test abnormalities or positive pregnancy tests) at 
any time point. A positive pregnancy test result is defined as serum or urine pregnancy test 
 
LFT values and ratios to ULN (i.e., ALT, AST, TBL and ALP) for SI units. The listing 
displays all LFT results over time for subjects with select LFT elevations (ALT or AST > 3x 
ULN; ALP or TBL > 2x ULN) at any time point.  
Refer to the protocol for laboratory tests of clinical interest, Refer to the Core SAP for toxicity 
grades and TLF contents. Laboratory test values are graded according to numeric laboratory test 
criteria using below toxicity grading scales:
Common Terminology Criteria for Adverse Events (CTCAE) if available; otherwise 
according to Division of Acquired Immune Deficiency Syndrome (DAIDS) Table for 
Grading the Intensity of Adult and Pediatric Adverse Events. These are based on SI units. 
6.4.2.1 
Laboratory Test Worst Abnormalities 
Frequency tables of the worst (highest) laboratory test abnormality for each graded laboratory 
test are provided for the following safety analysis periods and analysis sets: 
On-DBT for the DBT safety analysis set 
On-OL rimegepant for the OL rimegepant safety analysis set 
Follow-up for the follow-up safety analysis set.


 
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Grade 3 to 4 results support secondary objective #8. 
Frequency tables of laboratory test shift from baseline to the worst abnormality for each graded 
laboratory test are provided for the following safety analysis periods and analysis sets: 
On-DBT for the DBT safety analysis set 
On-OL rimegepant for the OL rimegepant safety analysis set. 
6.4.2.2 
LFT Elevations 
LFT Elevations 
Frequency tables of LFT elevations are provided for the following safety analysis periods and 
analysis sets:     
On-DBT for the DBT safety analysis set 
Post-DBT pre-OL rimegepant for the interim safety analysis set 
On-OL rimegepant for the OL rimegepant safety analysis set 
On-DB or OL rimegepant for the DB or OL rimegepant safety analysis set 
Follow-up for the follow-up safety analysis set.
Results support exploratory objective #9.
LFT Shifts from Baseline to Worst Elevation 
Frequency tables of LFT shifts from baseline to the worst (highest) LFT elevation are provided 
for the following safety analysis periods and analysis sets: 
On-DBT for the DBT safety analysis set 
On-OL rimegepant for the OL rimegepant safety analysis set. 
Exposure-adjusted Cumulative LFT Elevations 
Frequency tables of exposure-adjusted cumulative LFT elevations are provided for the following 
safety analysis periods and analysis sets: 
On-DB or OL rimegepant for the DB or OL rimegepant safety analysis set. 
Calculations use the same analysis period reference start and end dates as corresponding 
exposure-adjusted AEs (see Section 6.4.1.5).  
Time to First LFT Elevation 
Frequency tables of time to first LFT elevation are provided for subjects with select LFT 
elevations (ALT > 3x ULN; AST > 3x ULN; ALT or AST > 3x ULN) for the following safety 
analysis periods and analysis sets: 


 
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On-DB or OL rimegepant for the DB or OL rimegepant safety analysis set with on-DB or OL 
rimegepant LFT elevations 
o
Time categories are:  2, > 2 to  4, > 4 to 
8, > 8 to  12, > 12 to  16, > 16 to  20, > 
20 to  24, > 24 to  28, > 28 to  32, > 32 to  36, > 36 to  40, and > 40 weeks.  
o
Time to elevation is calculated as (LFT collection date  DB or OL rimegepant start date 
+ 1)/7. 
LFT Plots 
Evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plots are provided for the 
following safety analysis periods and analysis sets: 
On-DBT for the DBT safety analysis set by treatment group 
On-OL rimegepant for the OL rimegepant safety analysis set by treatment group/OL 
rimegepant. 
By-subject longitudinal LFT plots are provided for the safety analysis set with select LFT 
elevations in any safety analysis period. Study weeks are defined as study day/7, where study 
day is derived from the laboratory test collection date (see Section 7.3). Each figure also displays 
DB study drug dosing days and OL rimegepant dosing days using symbols along the x-axis (see 
Section 9.4), and denotes additional study milestones (e.g., start of the on-DBT safety analysis 
period, start of the on-OL rimegepant safety analysis period, and start of the follow-up safety 
analysis period) using vertical lines with their corresponding descriptions in footnotes.  
6.4.2.3 
Laboratory Test Changes from Baseline over Time
The table of values and changes from baseline in all hematology and serum chemistry laboratory 
tests is provided by treatment group and overall for the safety analysis set at the following time 
points: baseline; each scheduled visit through Week 12 and EOT in the on-DBT safety analysis 
period; each scheduled visit after Week 12 through Week 52 and EOT in the on-OL rimegepant 
safety analysis period; and Follow-up Week 2 in the follow-up safety analysis period. Results for 
overall are displayed only at baseline and time points in the on-OL rimegepant and follow-up 
safety analysis periods. 
Note that scheduled visits vary according to laboratory test. 
Refer to the Core SAP for (1) handling multiple values in an analysis visit window or on the 
same laboratory test collection date, and (2) deriving the EOT value in an on-treatment safety 
analysis period. 
6.4.3 
Vital Signs and Physical Measurement 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, temperature, and 
respiratory rate. Physical measurements include height, weight, and body mass index (BMI). 
These parameters are measured with a date at the following visits: Screening; Baseline; Weeks 4, 


 
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8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EOT; and Follow-up Week 2. Height is measured 
at the Screening Visit only.   
Refer to the Core SAP for TLF contents. 
6.4.3.1 
Vital Sign and Physical Measurement Changes from Baseline over Time 
The table of values and changes from baseline in vital sign and physical measurement parameters 
is provided by treatment group and overall for the safety analysis set at the following time points: 
baseline; each scheduled visit through Week 12 and EOT in the on-DBT safety analysis period; 
each scheduled visit after Week 12 through Week 52 and EOT in the on-OL rimegepant safety 
analysis period; and Follow-up Week 2 in the follow-up safety analysis period. Results for 
overall are displayed only at baseline and time points during the on-OL rimegepant and follow-
up safety analysis periods. 
Refer to the Core SAP for (1) handling multiple values in an analysis visit window or on the 
same measurement date, and (2) deriving the EOT value in an on-treatment safety analysis 
period. 
6.4.3.2 
Vital Sign and Physical Measurement Abnormalities
Frequency tables of vital sign and physical measurement abnormalities are provided for the 
following safety analysis periods and analysis sets:  
On-DBT for the DBT safety analysis set  
On-OL rimegepant for the OL rimegepant safety analysis set  
Follow-up for the follow-up safety analysis set. 
6.4.4 
Electrocardiograms 
ECG parameters include QRS, PR, QT, QTcB, QTcF, and ventricular heart rate. ECGs are 
measured with assessment date on ECG CRFs at the following visits: Screening; Baseline; 
Weeks 4, 16, 24, and 52/EOT; and Follow-up Week 2.  
Refer to the Core SAP for TLF contents. 
6.4.4.1 
ECG Changes from Baseline over Time 
The table of values and changes from baseline in ECG parameters is provided by treatment 
group and overall for the safety analysis set at the following time points: baseline; each 
scheduled visit through Week 12 and EOT in the on-DBT safety analysis period; each scheduled 
visit after Week 12 through Week 52 and EOT in the on-OL rimegepant safety analysis period; 
and Follow-up Week 2 in the follow-up safety analysis period. Results for overall are displayed 
only at baseline and time points in the on-OL rimegepant and follow-up safety analysis periods. 


 
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Refer to the Core SAP for (1) handling multiple values in an analysis visit window or on the 
same measurement date, and (2) deriving the EOT value in an on-treatment safety analysis 
period. 
6.4.4.2 
ECG Abnormalities 
Frequency tables of ECG abnormalities are provided for the following safety analysis periods 
and analysis sets:  
On-DBT for the DBT safety analysis set
On-OL rimegepant for the DB or OL rimegepant safety analysis set  
Follow-up for the follow-up safety analysis set. 
ECG abnormalities are presented together with vital sign and physical measurement 
abnormalities in the same tables (see Section 6.4.3.2).  
6.4.5 
C-SSRS 
The C-SSRS is a clinician administered questionnaire used to help establish immediate risk of 
suicide. The C-SSRS is administered at early termination and all visits except Pre-randomization. 
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.  
Refer to the Core SAP for calculation of C-SSRS parameters.  
Frequency tables of C-SSRS suicidality are provided for the following safety analysis periods 
and analysis sets:  
On-DBT for the DBT safety analysis set  
On-OL rimegepant for the OL rimegepant safety analysis set  
Follow-up for the follow-up safety analysis set. 
Refer to the Core SAP for calculation of C-SSRS parameters and TLF contents. 
6.4.6 
 Safety Narrative Subject Identifiers 
The by-subject listing of safety narrative subject identifiers is provided for the following select 
events as columns:   
Death in any analysis period for the enrolled analysis set   
SAE on DB or OL rimegepant or during follow-up for the DB or OL rimegepant safety 
analysis set 
AE leading to study drug discontinuation in any analysis period for the DB or OL rimegepant 
safety analysis set  


 
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Event of special interest on DB or OL rimegepant for the DB or OL rimegepant safety 
analysis set:  
ALT or AST > 3x ULN
ALT or AST 
x ULN and  2x baseline 
ALT or AST > 3x ULN concurrent with TBL > 2x ULN  
TBL > 2x ULN  
Select hepatic-related AE, i.e., PT containing cirrhosis, hepatic failure, hepatitis, 
jaundice, or liver failure
Suicidality AE.   
6.5
Outcomes Research 
Analyses are based on as-randomized treatment group for the DBT efficacy analysis sets.  
Outcomes research questionnaires MSQoL, MIDAS, and EQ-5D-5L are assessed using the 
eDiary at Baseline, Week 12, Week 24, and Week 52.  
Measurements are slotted into analysis periods and analysis visits using the eDiary finding date 
and the following steps:
1) Measurements are slotted into the pretreatment, DBT outcomes research, and OL rimegepant 
outcomes research analysis periods. 
2) Measurements are slotted into analysis visits in the analysis periods listed in the previous step 
(see Table 5). 
Refer also to the Core SAP for details about measurement slotting. See Sections 6.2.5, 7.2, and 
7.3 for definitions of baseline, analysis periods, and analysis visit windows, respectively.   
By-subject listings of outcomes research questionnaires (i.e., MSQoL, MIDAS, and EQ-5D-5L) 
are provided for the enrolled analysis set. The listing displays values and changes from baseline 
for the following: MSQoL domain scores; MIDAS total, absenteeism, and presenteeism scores; 
EQ-5D-5L VAS score. 
Refer to the Core SAP for the following: detailed descriptions of these questionnaires and rating 
scales; calculating scores and imputing missing data; deriving categories; handling multiple 
questionnaires or rating scale values in an analysis visit window or on the same assessment date; 
and TLF contents. 
6.5.1 
MSQoL 
The MSQoL consists of 14 items across the following 3 domains: (1) restrictive role function, (2) 
preventative role function and (3) emotional function.  


 
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Descriptive Analyses  
The table of values and changes from baseline in scores is provided by treatment group and 
overall for each domain for the DBT efficacy analysis set at the following time points: baseline; 
Week 12 of the DBT outcomes research analysis period; Week 24 and Week 52 in the OL 
rimegepant outcomes research analysis period. Results for overall are displayed only at baseline 
and time points in the OL rimegepant outcomes research analysis period. Results support 
exploratory objective #8. 
The frequency table of MSQoL domain score reduction from baseline categories is provided by 
treatment group and overall for the DBT efficacy analysis set at the following time points: Week 
12 of the DBT outcomes research analysis period; Week 24 and Week 52 in the OL rimegepant 
outcomes research analysis period. Results for overall are displayed only at time points in the OL 
rimegepant outcomes research analysis period. 
Treatment Group Comparisons  
Analyses of each domain are based on the DBT efficacy analysis set with paired data, i.e., 
nonmissing domain scores at both baseline and Week 12 of the DBT outcomes research analysis 
period. 
For each domain, treatment groups are compared using a linear regression model with the 
following attributes: 
Variables: Week 12 change from baseline in the score as the dependent variable; baseline 
score as a covariate; treatment group and randomization stratum as fixed effects.  
SE estimation method: See Section 6.3.1.1.. 
The table provides n (i.e., number of subjects with paired data) and the following model 
estimates for each domain: 
LSM change from baseline at Week 12, SE, and 95% CI for each treatment group  
Difference in LSM changes from baseline at Week 12 between each rimegepant treatment 
group and placebo (rimegepant  placebo), SE, 95% CI, and p-value.  
Results for the restrictive role function support secondary objective #5, whereas results for the 
other domains support exploratory objective #8. 
See Section 9.3.2 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional linear regression models that exclude 
randomization stratum as a fixed effect. 
6.5.2 
MIDAS 
The MIDAS is a retrospective, patient-administered, 5-item questionnaire that measures 
headache-related disability as lost time due to headache from paid work or school, household 
work, and non-work activities.  


 
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Descriptive Analyses 
The table of values and changes from baseline in total, absenteeism, presenteeism, and item 
scores is provided, and has a similar format as the one described in Section 6.5.1. 
Results support exploratory objective #8.
Treatment Group Comparisons 
Analyses of each score (total, absenteeism, presenteeism) are based on the DBT efficacy analysis 
set with scores at both baseline and Week 12 of the DBT outcomes research analysis period. 
For each score, treatment groups are compared using a linear regression model with the same 
attributes as the one described in Section 6.5.1. The table has the same format. 
Results for the total score support secondary objective #6, whereas results for the other scores 
support exploratory objective #8. 
6.5.3 
EQ-5D-5L 
The EQ-5D-5L is a 2-
part, subjects rate their current level of function in 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. In the second part, subjects rate their health 
on a VAS scale from 0 (worst imaginable health) to 100 (best imaginable health).  
Descriptive Analyses 
The table of values and changes from baseline in the VAS and utility index scores is provided, 
and has a similar format as the one described in Section 6.5.1. The utility index score is 
calculated from the official Japanese tariff based on time trade-off data.3  
The frequency table of EQ-5D-5L dimension function level is provided by treatment group and 
overall for the DBT efficacy analysis set at the following time points: baseline; Week 12 of the 
DBT outcomes research analysis period; Week 24 and Week 52 of the OL rimegepant outcomes 
research analysis period. Results for overall are displayed only at baseline and time points in the 
OL rimegepant outcomes research analysis period. 
Results support exploratory objective #8.
Treatment Group Comparisons 
Analyses are based on the DBT efficacy analysis set with VAS scores at both baseline and Week 
12 of the DBT outcomes research analysis period. 
Treatment groups are compared using a linear regression model with the same attributes as the 
one described in Section 6.5.1. The table has the same format. 
Results support secondary objective #7. 


 
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7 CONVENTIONS 
7.1
Derived Dates 
Derived dates are defined as follows: 
Screening visit date: visit date from the Visit Date  
eDiary efficacy date: complete datepart{eDiary finding date/time}  1 day from the eDiary 
headache report 
Study drug start date: earliest complete dose date from IP Administration 
DB or OL CRF 
with number of tablets taken > 0. This is an analysis period reference date. 
Study drug end date: latest complete dose date from IP Administration  DB or OL CRF with 
number of tablets taken > 0 
Study drug last date:  
Before the final database lock: study drug end date derived only for subjects who have 
either (1) or (2): 
Status CRF, and 
-
phase on the DB Subject Status CRF}, and missing OL rimegepant start date 
Status or Follow-up Subject Status CRF 
Final database lock: study drug end date 
This is an analysis period reference date. 
DB study drug start date: earliest complete dose date from IP Administration  DB or OL 
CRF records with number of tablets taken > 0 and valid DB wallet number. This is an 
analysis period reference date. 
DB study drug end date: latest complete dose date from IP Administration  DB or OL CRF 
records with number of tablets taken > 0 and valid DB wallet number 
DB study drug last date:  
Before the first database lock: DB study drug end date derived only for subjects with 
Subject Status, or Follow-up Subject Status CRF  
First database lock or after: DB study drug end date 
This is an analysis period reference date. 
OL rimegepant start date: earliest complete dose date from IP Administration  DB or OL 
CRF records with number of tablets taken > 0 and valid OL wallet number. This is an 
analysis period reference date. 


 
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OL rimegepant end date: latest complete dose date from IP Administration 
DB or OL CRF 
records with number of tablets taken > 0 and valid OL wallet number 
OL rimegepant last date: 
Before the final database lock: OL rimegepant end date derived only for subjects with 
Follow-up Subject Status CRF 
Final database lock: OL rimegepant end date 
This is an analysis period reference date. 
DB or OL rimegepant start date: study drug start date for subjects whose as-treated DB 
treatment group is rimegepant; OL rimegepant start date for subjects whose as-treated DB 
treatment group is placebo. This is an analysis period reference date.
DB or OL rimegepant end date: study drug end date for subjects whose as-treated DB 
treatment group is rimegepant; OL rimegepant end date for subjects whose as-treated DB 
treatment group is placebo 
DB or OL rimegepant last dose date: study drug last date for subjects whose as-treated DB 
treatment group is rimegepant; OL rimegepant last date for subjects whose as-treated DB 
treatment group is placebo. This is an analysis period reference date. 
OP start date: earliest of the following: screening visit date  1 day; eDiary efficacy date. 
This is an analysis period reference date. 
OP end date:  
If the study drug start date is nonmissing: study drug start date  1 day 
If the study drug start date is missing and the randomization date is nonmissing: 
randomization date  1 day 
If both study drug start date and randomization date are missing: last contact date 
This is an analysis period reference date.
Last contact date:  
1. Earliest complete death date from the AE CRF, if it exists. 
2. Otherwise, the latest complete date of the following: AE start or end; ECG; eDiary 
finding; informed consent; dose; IWRS randomization; laboratory test collection; non-
study medication start or end; physical exam; physical measurement; procedure; rating 
scale; questionnaire; vital sign; visit.  
3. If the last contact date is after the most recent raw database creation date, then it is set to 
the most recent raw database creation date. 
Death date: refer to the Core SAP. 
No imputations are performed on these derived dates unless otherwise specified.  


 
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Refer to the Core SAP for the definition of complete dates.  
7.2
Analysis Periods 
Measurements are slotted into analysis periods based on comparing measurement dates to 
analysis period reference dates (time is not applicable). 
Analysis periods are defined according to endpoints as follows: 
eDiary efficacy endpoints (migraine days, acute migraine-specific medication days, acute 
migraine medication days, headache days)
OP: eDiary efficacy date on or after the OP start date through the OP end date. Note that 
this is a subset of the pretreatment analysis period. 
28-day OP: eDiary efficacy date on or after the OP start date through the earlier of {OP 
start date + 27 days; OP end date}. Note that this is a subset of the OP analysis period, 
and is used only to assess efficacy data issues during the OP as relevant protocol 
deviations. 
On-DBT efficacy:  
If the DB study drug last date or OL rimegepant start date is not missing: eDiary 
efficacy date on or after the DB study drug start date through the earlier of {DB study 
drug last date + 1 day; OL rimegepant start date  1 day} 
If the DB study drug last date and OL rimegepant start date are both missing: eDiary 
efficacy date on or after the DB study drug start date 
This period is used to assess efficacy during the DBT Phase. 
On-OL rimegepant efficacy:  
If the OL rimegepant last date is not missing: eDiary efficacy date on or after the OL 
rimegepant start date through the OL rimegepant last date + 1 day 
If the OL rimegepant last date is missing: eDiary efficacy date on or after the OL 
rimegepant start date
Pretreatment characteristics and safety endpoints* 
Pretreatment: This period is used to derive baseline values.  
On-DBT safety: This period is used to assess safety endpoints on DBT for the DBT 
safety analysis set.  
Post-DBT pre-OL rimegepant safety: This period is used to assess safety endpoints 
during the interim period (i.e., post-DBT pre-OL rimegepant) for the interim safety 
analysis set.
On-OL rimegepant safety: This period is used to assess safety endpoints on OL 
rimegepant for the OL rimegepant safety analysis set. 
On-DB or OL rimegepant safety: This period is used to assess safety endpoints on DB or 
OL rimegepant for the DB or OL rimegepant safety analysis set. 


 
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On-treatment safety: This period is used to define analysis visit windows.  
Follow-up safety: This period is used to assess safety endpoints during follow-up for the 
follow-up safety analysis set. 
Outcomes research endpoints (MSQoL, MIDAS, EQ-5D-5L) * 
DBT outcomes research: This period is used to assess outcomes research endpoints 
during the DBT Phase for the DBT efficacy analysis set. 
OL rimegepant outcomes research:  This period is used to assess outcomes research 
endpoints during the OLE Phase for the OL rimegepant efficacy analysis set. 
Phase 2/3/4 multiple-dose studies with both DBT and OLE Phases. See Section 7.1 for derived 
dates for determining analysis periods.  
7.3
Analysis Visit Windows 
Refer to C4951021 Protocol Section 4.3 (Tables 1 and 2) for the schedule of assessments.  
Refer to the Core SAP for defining randomization days, study days, rimegepant study days, and 
follow-up days in Phase 2/3/4 multiple-dose studies with both DBT and OLE Phases. 
Analysis visit windows are shown in Table 5. 
Table 5 
Analysis Visit Windows 
Analysis Period 
Analysis Visit 
Abbreviation in Listings 
Analysis Day 
Analysis Visit Window  
Target Day 
Pretreatment 
PRETRT
Randomization Day 
 
Screening * 
 
 -7 
 
Pre-randomization * 
Prerand 
-6 to -1 
 
Baseline * 
 
1 
 
Post-randomization @ 
Postrand 
 2 
 
Outcomes Research /On-
treatment Safety 
Outcomes Research: DBT 
or OLRMG/ Safety: DBT, 
INT, or OLRMG  
Study Day 
 
Week 2 
 
2 to 21 
14 
Week 4 
 
22 to 42 
28 
Week 8 
 
43 to 70 
56 
Week 12 
 
71 to 91 
84 
Week 14 
 
92 to 105 
98 
Week 16 
 
106 to 126 
112 
Week 20 
 
127 to 154 
140 


 
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Analysis Period
Analysis Visit 
Abbreviation in Listings 
Analysis Day
Analysis Visit Window  
Target Day 
Week 24 
 
155 to 182 
168 
Week 28 
 
183 to 210 
196 
Week 32 
 
211 to 238 
224 
Week 36 
 
239 to 266 
252 
Week 40 
 
267 to 294 
280 
Week 44 
 
295 to 322 
308 
Week 48 
 
323 to 350 
336 
Week 52 
 
351 to 378 
364 
Extension @ 
 
 379 
 
Follow-up Safety 
FU 
Follow-up Day 
 
Follow-up Week 2 
FU Week 2 
8 to 35 
14 
Follow-up Extension @ 
FU Ext 
 36 
 
 
@ Denotes an extended visit in the analysis period and is displayed only in listings 
Study days are used to define analysis visit windows in all analysis periods. Follow-up days are 
used to define analysis visit windows in the follow-up safety analysis period. 
8 CONTENT OF REPORTS 
See Section 1.2 for the timing of database locks and reports. 
8.1
PCD Final CSR 
The following TLFs are produced for the PCD final CSR, which focuses on efficacy, safety, and 
outcomes research endpoints during the DBT Phase: 
Section 6.2 Study Population: all tables and listings 
Section 6.3 Efficacy: listing; tables and figures of endpoints during the DBT Phase  
Section 6.4 Safety: 
All listings  
on-DBT, and post-DBT pre-OL rimegepant safety analysis periods: all tables and figures 
On-OL rimegepant safety analysis period: tables of AE overview, AEs by worst intensity, 
AEs related to study drug by worst intensity, SAEs, AEs leading to study drug 
discontinuation, worst laboratory test abnormalities, and LFT elevations. 
Follow-up safety analysis period: tables of AE overview, AEs by worst intensity, and 
SAEs. 


 
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Section 6.5 Outcomes Research: all tables and listings.
8.2
Week 24 Final CSR 
The following TLFs are produced for the Week 24 final CSR, if requested by a regulatory 
agency, which focuses on efficacy, safety, and outcomes research endpoints during the OLE 
Phase: 
Section 6.2 Study Population:  
All listings 
Sections 6.2.1, 6.2.3.2, 6.2.3.3, 6.2.3.4, 6.2.3.5, and 6.2.4: all tables 
Sections 6.2.5, 6.2.6.1, and 6.2.6.2: tables for the OL rimegepant safety and DB or OL 
rimegepant safety analysis sets 
Section 6.2.6.3: all tables 
Section 6.3 Efficacy: tables, figures and listings of endpoints during the OLE Phase; line plot 
of migraine day reduction across the DBT and OLE Phases combined 
Section 6.4 Safety: 
All listings  
On-DBT and post-DBT pre-OL rimegepant safety analysis periods: all tables and figures 
On-OL rimegepant safety analysis period: all tables and figures
On-DB or OL rimegepant safety analysis period: all tables   
Follow-up safety analysis period: all tables. 
Section 6.5 Outcomes Research: listing; all tables except those of treatment comparisons. 
8.3
LSLV Final CSR 
All TLFs described in this SAP are produced for the LSLV final CSR.
9 APPENDICES 
9.1
Relevant Protocol Deviations 
Relevant eligibility protocol deviations include the following categories:  
Randomized or treated with study drug under > 1 subject identifier. These are identified from 
the external Microsoft Excel file of protocol deviations from the data management vendor. 
Migraine history issue, defined as any of the following subcategories: 
o
question about experiencing migraines for  1 year prior to screening. 


 
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o
 3 or  19 moderate or severe migraine attacks per month in the 3 months prior to 
screening
These are based on the Migraine History CRF. 
Medical history, defined as any of the following subcategories: 
o
Type of migraine: basilar; hemiplegic; or retinal, if consented to Protocol Version 4 or 
higher 
o
Active chronic pain syndrome or other pain syndromes other than migraine present at 
screening
o
Dementia or significant neurological disorder other than migraine present at screening 
o
Major depressive disorder with atypical antipsychotics taken as non-study prior 
medications, schizophrenia, bipolar disorder, or borderline personality disorder present at 
screening. PTs must contain any of the following: major depress; schizophrenia; bipolar 
disorder; borderline personality disorder. Refer to the Core SAP for atypical 
antipsychotics and non-study prior medication type. 
o
Active hepatic or biliary disorder present at screening 
o
Gastric or small intestinal surgery. 
For each subcategory, PTs are displayed alphabetically as additional subcategories. Unless 
otherwise specified, PTs are identified by the sponsor medical lead or designee from 
reviewing a list of unique medical history SOC and PTs. Active medical history status is also 
identified by the sponsor medical lead or designee from reviewing by-subject listings of 
medical history and AEs. 
Present at screening is defined as medical history end date of ongoing (refer to the Core SAP) 
or on or after the informed consent date. 
Finding out of range, defined any as any of the following subcategories: 
o
Females with a positive pregnancy test on or after informed consent 
o
Estimated glomerular filtration rate (eGFR) 
40 mL/min/1.73m2 during pretreatment *
o
BMI  33 kg/m2 during pretreatment, if consented to Protocol Version 3 or lower * 
o
BMI > 35 kg/m2 during pretreatment, if consented to Protocol Version 4 or higher * 
o
C-SSRS suicidal ideation with active intent or plan to act, or suicidal behavior present 
response to any of the following C-SSRS 
questions during pretreatment: 
Suicidal ideation question 4 (active suicidal ideation with some intent to act, without 
specific) or 5 (active suicidal ideation with specific plan and intent) 
Suicidal behavior question 1 (actual attempt), 3 (interrupted attempt), 4 (aborted 
attempt), 5 (preparatory acts or behavior), or 6 (suicidal behavior). 
analysis period must meet the deviation criteria in order to be considered a deviation. 


 
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Efficacy data issue during the first 28 days of the OP for the full analysis set, defined as any 
of the following subcategories: 
o
 3 migraine days  
o
 19 headache days 
o
 23 days of eDiary efficacy data (see Section 9.2.2). 
These are assessed during the 28-day OP analysis period (see Section 7.2). Migraine days 
and headache days are absolute, not prorated to 28 days per month (see Sections 9.2.5 and 
9.2.6), and of total pain intensity. 
Relevant subject management protocol deviations include the following categories: 
Stable prophylactic migraine medication use through randomization discrepant between 
IWRS and CRF data, defined as any of the following subcategories: 
o
IWRS randomization stratum of yes, but no stable prophylactic migraine medication 
taken through randomization 
o
IWRS randomization stratum of no, but stable prophylactic migraine medication taken 
through randomization.  
See Section 6.2.5.4 for the definition of non-study stable medication through randomization. 
Prophylactic migraine medication usage issue, defined as any of the following subcategories: 
o
Prophylactic migraine medication started or stopped from 12 weeks before informed 
consent to randomization. Defined as informed consent date  84 days  imputed non-
study medication start or end date  IWRS randomization date. 
o
as > 1 unique preferred name. 
DB study drug dosing issue, defined as any of the following subcategories (see Section 
6.2.6.2): 
o
DB study drug taken but not randomized 
o
> 1 DB tablet taken on any 1 day 
o
DB tablet count compliance < 80% from DB study drug start to later of last scheduled 
DBT Phase visit or DB study drug end/OL rimegepant start 
o
Incorrect DB study drug taken 
OL rimegepant dosing issue, defined as any of the following subcategories (see Section 
6.2.6.2) 
o
OL rimegepant tablet count compliance < 80% from OL rimegepant start to later of last 
scheduled OLE Phase visit or OL rimegepant end  
o
> 1 OL rimegepant tablet taken on any 1 day 
o
OL rimegepant start on or before DB study drug end 


 
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o
OL rimegepant taken but DB study drug never taken. 
eDiary usage compliance < 80% from DB study drug start to later of last scheduled DBT 
Phase visit or DB study drug end (see Section 6.2.6.2) 
eDiary usage compliance < 80% from OL rimegepant start to later of last scheduled OLE 
Phase visit or OL rimegepant end (see Section 6.2.6.2) 
Prohibited non-study medications, defined as any of the following subcategories: 
o
Atypical antipsychotics taken on or after informed consent #  
o
Botulinum toxin type A taken on or after informed consent 
o
Butterbur root or extract taken up to 14 days before randomization or afterward 
o
Calcitonin gene-related peptide (CGRP) antagonist monoclonal antibody or small 
molecule taken on or after informed consent # 
o
Ergotamine taken on or after informed consent 
o
Lamotrigine taken on or after informed consent 
o
Lasmiditan taken up to 14 days before randomization or afterward 
o
Narcotic (barbiturate or opioid) taken up to 2 days before randomization or afterward # 
o
Select moderate or strong cytochrome P450 3A4 (CYP3A4) inducer taken on or after 
informed consent # 
o
Select strong CYP3A4 inhibitor taken on or after informed consent #  
o
Traditional Chinese medicine taken up to 14 days before randomization or afterward#. 
These are identified by the sponsor medical lead or designee from reviewing a list of 
unique therapeutic class and preferred names. 
o
Triptan as non-study OL rimegepant concomitant medication (see Section 6.2.6.3) #. 
additional subcategories. Medications taken up to X days before a reference date or afterward are 
defined as those with imputed medication start date or imputed end date  reference date  X.  
Refer to the Core SAP for additional details about prohibited non-study medications, except for 
CYP3A4 inducers and inhibitors which are defined below. 
 
Medication Group 
Preferred Name 
CYP3A4 inducer, select 
moderate 
CYP3A4 and P-gp Inducers and Inhibitors.xlsx (latest version) 
CYP3A4 inducer, select 
strong 
Preferred name in column A of 
CYP3A4 and P-gp Inducers and Inhibitors.xlsx (latest version) 
CYP3A4 inhibitor, select 
strong 
CYP3A4 and P-gp Inducers and Inhibitors.xlsx (latest version) 


 
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randomization date is missing, then the study drug start date is used. 
The protocol version to which subjects consented is determined from the Informed Consent CRF. 
9.2
eDiary Efficacy 
9.2.1 
Efficacy Parameters 
On a given day, subjects use the eDiary to provide responses to the following efficacy 
parameters occurring yesterday:  
Headache (yes, no) 
associated symptoms are collected: 
o
Lasts at least 30 minutes (yes, no) 
o
Pain severity (mild, moderate, severe) 
o
Unilateral (yes, no) 
o
Pulsating (yes, no) 
o
Worsen or avoid physical activity (yes, no) 
o
Nausea (yes, no) 
o
Vomiting (yes, no)
o
Photophobia (yes, no) 
o
Phonophobia (yes, no) 
Aura (yes, no) 
about taking medications to treat headache or aura are collected: 
o
Triptan (yes, no) 
o
Ergotamine (yes, no) 
o
Other medication (yes, no). 
These efficacy parameters are collected together as a set with the same eDiary finding date/time 
for a subject.  It is expected that subjects have only 1 set of efficacy parameters collected on a 
given eDiary finding date. Handling of multiple sets on the same date are discussed in 
subsequent sections. 
9.2.2 
eDiary Efficacy Data Day 
A day of eDiary efficacy data is defined as any complete eDiary efficacy date (see Section 7.1).  


 
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9.2.3 
Acute Migraine Medication Day 
An acute migraine medication day is defined as a either (1) or (2):  
1.
Acute migraine-specific medication day (Section 9.2.4) 
2.
Migraine day (Section 9.2.5
medications to treat headache or aura 
Thus, acute migraine medication days are a subset of migraine days (Section 9.2.5). If there are 
multiple sets of efficacy parameters on the same finding date, then data from all sets are used 
cumulatively to assess acute migraine medication day status on that day, regardless of finding 
triptan on that day, then the subject is considered to have taken triptan on that day. 
9.2.4 
Acute Migraine-specific Medication Day 
An acute migraine-specific medication day is defined as a day of eDiary efficacy data with a 
aura. 
Thus, acute migraine-specific medication days are a subset of acute migraine medication days 
and migraine days (see Sections 9.2.3 and 9.2.5, respectively). If there are multiple sets of 
efficacy parameters on the same finding date, then data from all sets are used cumulatively to 
assess acute migraine-specific medication day status on that day, regardless of finding time. 
9.2.5 
Migraine Day 
A migraine day is defined as a day of eDiary efficacy data with either (1) or (2) or (3): 
1)
 
a.
Headache lasting  
 30 
minutes 
b. Meeting  1 of the following criteria (i or ii): 
i.
 2 of the following pain features: 
1.
 
2.
 
3. Moderate or severe pain intensity 
4.
or avoid physical activity  
ii.
 1 of the following associated symptoms: 
1.
 
2.
 


 
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3.
photophobia and phonophobia 
2) Acute migraine-specific medication day (see Section 9.2.4) 
3) Non-scheduled OL rimegepant dosing day (see Section 9.4). 
Migraine days are a subset of headache days (see Section 9.2.6). 
If there are multiple sets of efficacy parameters on the same finding date, then data from all sets 
are used cumulatively to assess migraine day status on that day, regardless of finding time. 
Migraine pain intensity is set to the greatest pain intensity on that day.  
9.2.6 
Headache Day
A headache day is defined as a day of eDiary efficacy data with either (1), (2), or (3): 
1) Migraine day (see Section 9.2.5)
2) Headache that lasts  
 30 minutes 
3) Headache of any duration for which acute headache treatment is administered: Meeting both 
of the following criteria (a and b): 
a)
 
b)
aura (i.e., triptan, ergotamine, or other medications). 
If there are multiple sets of efficacy parameters on the same finding date, then data from all sets 
are used cumulatively to assess headache day status on that day, regardless of finding time. 
Headache pain intensity is set to the greatest pain intensity on that day. 
9.3
SAS Code
9.3.1 
Linear Mixed Effects Model with Repeated Measures 
Consider the following variables used to evaluate the primary efficacy endpoint using a linear 
mixed effects model with repeated measures: 
mdmchg: change from the OP in migraine days per month; continuous variable 
mdmop: migraine days per month during the OP; continuous variable 
month: month; categorical variable with levels of 1, 2, and 3 
rndstr: randomization stratum; categorical variable with levels of 1 and 2 to denote yes and 
no, respectively
trt: treatment group; categorical variable with levels of 1 and 2 to denote rimegepant and 
placebo, respectively 
usubjid: unique subject identifier; categorical variable. 
 


 
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Then the SAS code is as follows: 
proc mixed data = xxx empirical; 
class usubjid rndstr trt month; 
model mdmchg = mdmop rndstr trt month trt*month; 
repeated month / subject = usubjid type = un; /* unstructured covariance */ 
lsmeans trt trt*month / alpha = 0.05 cl diff; 
run; 
9.3.2 
Linear Regression Model 
Consider the following variables used to evaluate any of the last 3 secondary outcomes research 
endpoints using a linear regression model: 
scorechg: score change from baseline at Week 12; continuous variable 
rndstr: randomization stratum; categorical variable with levels of 1 and 2 to denote yes and 
no, respectively
scorebl: baseline score; continuous variable 
trt: treatment group; categorical variable with levels of 1 and 2 to denote rimegepant and 
placebo, respectively 
usubjid: unique subject identifier; categorical variable. 
Then the SAS code is as follows: 
proc mixed data = xxx empirical; 
class usubjid rndstr trt; 
model scorechg = scorebl rndstr trt; 
repeated / subject = usubjid; 
lsmeans trt / alpha = 0.05 cl diff; 
run; 
9.4
Study Drug Dosing Day 
The sites report the start date for administration of the IP in the phase in the IP Administration  
DB and OL CRFs. Based on the start date, the data management vendor autopopulates records 
with dosing dates from the start date through 12 weeks on the IP Administration  DB CRF and 
though 40 weeks on the IP Administration  OL CRF. Sites can report additional dose dates 
beyond the autopopulated records if needed. On each dose date, sites also report the number of 
tablets taken and dosing day type (scheduled or non-scheduled). During either the DBT or OLE 
Phase, is expected that sites report number of tablets taken  0 on scheduled dosing days, where 
taken > 0 on non-scheduled dosing days only when subjects dosed PRN.  
A DB study drug dosing day is defined as a day with nonmissing dose date on which  1 DB 
tablet of study drug was taken, which is determined using valid DB wallet numbers. DB study 


 
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Otherwise, DB study drug dosing days are classified as non-scheduled. 
An OL rimegepant dosing day is defined as a day with nonmissing dose date on which  1 tablet 
of OL rimegepant study drug was taken, which is determined using valid OL wallet numbers. OL 
rimegepant dosing days are classified as scheduled or non-scheduled analogously.
Non-study drug dosing days are days on which no study drug was taken (i.e., number of tablets 
taken is 0 or missing).
All days in the OL rimegepant efficacy analysis period are classified as either planned scheduled 
or planned non-scheduled OL rimegepant dosing days. A planned scheduled OL rimegepant 
dosing day is defined as any of the following: 
Scheduled OL rimegepant dosing day 
Non-study drug dosing day that is (1) an even number of days after a scheduled OL 
rimegepant dosing day and (2) before the next OL rimegepant dosing day, if it exists 
Non-study drug dosing day that is (1) an odd number of days after a non-scheduled OL 
rimegepant dosing day and (2) before the next OL rimegepant dosing day, if it exists. 
All other days in the OL rimegepant efficacy analysis period are classified as planned non-
scheduled OL rimegepant dosing days.  
For example, suppose days 1, 3, 5, 8, and 10 are scheduled OL rimegepant dosing days and days 
6 and 14 are non-scheduled OL rimegepant dosing days. Then: 
Days 1, 3, 5, 7, 8, 10, 12, and 15 are planned scheduled OL rimegepant dosing days. 
Days 2, 4, 6, 9, 11, 13, and 14 are planned non-scheduled OL rimegepant dosing days. 
10  REFERENCES  
 
1
 
2
 
3. Ikeda S, Shiroiwa T, Igarashi A, et al. Developing a Japanese version of the EQ-5D-5L value 
set. Journal of the National Institute of Public Health 2015;64(1):47-55.